European Journal of Medicinal Chemistry 137 (2017) 504e544

Contents lists available at ScienceDirect

European Journal of Medicinal Chemistry

journal homepage: http://www.elsevier.com/locate/ejmech

Review article

Drug development against tuberculosis: Impact of alkaloids*

Shardendu K. Mishra a, b, 1, Garima Tripathi a, 2, 1, Navneet Kishore a, 3, Rakesh K. Singh c,
Archana Singh a, Vinod K. Tiwari a, *
a
Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005, Uttar Pradesh, India
b
Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, Uttar Pradesh, India
c
Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India

a r t i c l e i n f o a b s t r a c t

Article history: Despite of the advances made in the treatment and management, tuberculosis (TB) still remains one of
Received 4 April 2017 main public health problem. The contrary effects of first and second-line anti-tuberculosis drugs have
Received in revised form generated extended research interest in natural products in the hope of devising new antitubercular
26 May 2017
leads. Interestingly, plethoras of natural products have been discovered to exhibit activity towards
Accepted 2 June 2017
various resistant strains of M. tuberculosis. Extensive applications of alkaloids in the field of therapeutics
Available online 3 June 2017
is well-established and nowday's researches being pursued to develop new potent drugs from natural
sources for tuberculosis. Alkaloids are categorized in quite a few groups according to their structures and
Keywords:
Alkaloids
isolation from both terrestrial and marine sources. These new drugs might be a watershed in the battle
Tuberculosis against tuberculosis. This review summarizes alkaloids, which were found active against Mycobacteria
Mycobacterium tuberculosis since last ten years with special attention on the study of structure-activity relationship (SAR) and mode
Antimycobacterial agents of action with their impact in drug discovery and development against tuberculosis.
Multi drug resistant tuberculosis © 2017 Elsevier Masson SAS. All rights reserved.
Natural products
Drug development

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505
2. Clinical manifestations and pathogenesis of tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506
2.1. Clinical manifestations of tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506
2.2. Pathogenesis of tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506
3. Existing therapies and tools to combat tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507
3.1. Pioneer drugs in the treatment of tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507
4. Resistance to current antimycobacterial agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508
4.1. Multi drug resistance tuberculosis (MDR-TB) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508
4.2. Extensively drug resistant tuberculosis (XDR-TB) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508
4.3. Totally drug resistant tuberculosis (TDR-TB) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508
5. Novel antituberculosis drugs in pipeline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509
6. Common molecular targets for antimycobacterial agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511
6.1. Protein synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511
6.2. Nucleic acids biosynthesis and DNA gyrase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513
6.3. Nucleotide biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513
6.4. Cell wall macromolecule biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513
6.5. Fatty acid biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514

*
This manuscript is dedicated to Prof. (Dr) Rama P. Tripathi, Senior Scientist at CSIR-Central Drug Research Institute, Lucknow, India.
* Corresponding author.
E-mail address: Tiwari_chem@yahoo.co.in (V.K. Tiwari).
2
Present address: Department of Chemistry, Indian Institute of Technology, Kanpur, India.
3
Present address: Department of Plant Science, University of Pretoria, Pretoria-0002, South Africa.
1
Author contributed equally.

http://dx.doi.org/10.1016/j.ejmech.2017.06.005
0223-5234/© 2017 Elsevier Masson SAS. All rights reserved.
 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544 505

6.6. Isocitrate lyase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514

6.7. ATP biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515
7. Assay and diagnostic tools for tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515
7.1. Assays for tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515
7.1.1. In vivo assay for Mycobacterium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515
7.1.2. In vitro assay for Mycobacterium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515
7.1.3. Toxicity and selectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518
7.2. Diagnostic tools for tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518
7.2.1. Sputum investigation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518
7.2.2. Tuberculin test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518
7.2.3. Radiographic investigation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518
7.2.4. Nucleic acid techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518
8. Plants: a harry potter stick for tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518
9. Alkaloids with significant antimycobacterial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 519
9.1. Indole alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 519
9.2. Pyrrole alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 520
9.3. Carbazole alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 522
9.4. Indoloquinoline alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 522
9.5. Manzamine alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523
9.6. Quinoline alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523
9.7. Isoquinoline alkaloid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524
9.8. Pyrrolo [2,1-b]quinazoline alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525
9.9. Cyclostelletamine alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526
9.10. Pyridoacridone alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527
9.11. Aza-anthraquinone alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 528
9.12. Pyrrolidine alkaloid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 529
9.13. Imide alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530
9.14. Piperidine alkaloid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530
9.15. Cyclopeptide alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531
9.16. Agelasine alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531
9.17. Polycyclic guanidine alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532
9.18. Oxazole alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532
9.19. Diterpenoid b-lactam alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533
9.20. Miscellaneous alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 534
10. Conclusion and future purspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536
Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536

1. Introduction to the sudden rise of new TB cases supported by the introduction of

Human Immunodeficiency Virus (HIV) resulting in millions of
Since inception tuberculosis (TB) has been the most challenging deaths every year [12]. Around one-third of the world's population
disease in human era that is caused by Mycobacterium tuberculosis is presently informed to be infected with M. tuberculosis. World
(M.Tb), an acid-fast bacillus, which persists in host body for the Health Organization, 2014 survey, revealed on TB patients that the
longer period without any indication of disease [1e3]. The primary estimated 85% cases happened in Asia (58%) and Africa (28%), while
cause for the survival of this bacillus is its unique property to around 14% cases arised in the rest of the world [13e15]. According
develop resistance against the drugs discovered till today [4,5]. In to the WHO (2016) annual report on TB, 2.84 million Indians con-
immunocompromised patient, this bacillus start a silent warfare, tracted the disease in 2015 alone and thus India bears the
which eventually transformed into an assault leading to the un- maximum number of TB patients with an estimated 79,000 persons
controlled growth of bacteria (nearly 1013 organisms) [6,7]. The becoming sick with this disease each year [16].
period of tuberculosis drug discovery and current researches in Immuno deficiency due to HIV clears the path for tuberculosis
pipeline has been associated with multilateral agencies and various persistence by leading towards an immunocompetent person
non-governmental organizations for technical assistance as well as transformation into a horrifying assault [17,18]. HIV prevalence
pharmaceutical companies developed new strategy to alleviate with tuberculosis is marked increasing from last two decades and
tuberculosis [8e10]. fueled tuberculosis outbreak. The available regimen for the tuber-
It has been considered a sickness of death for many years with culosis was discovered in between 1950 and 1975 resulting in a
relatively rare cases in the developed countries. Tuberculosis re- drastic decrease in the disease, but the emergence of multi-drug
mains a huge problem in economically weaker section (below resistant (MDR) leads to a sudden increase in disease graph
poverty line) in developing countries [11]. This “White Plague” is a which is alarming statistics [19,20]. Today's treatment is more
critical challenge not only for medical but also from the social point problematic to the clinicians due to resistance to more than two
of view for the current situation, too. Virtually, every year about 1.5 antimycobacterial drugs leading to development of multi-drug
million people dies all over the world, and around 9e9.5 million of resistant tuberculosis (MDR-TB) [21,22].
new TB patient's registration are observed. Recently, World Health However, owing to the advent of drug-resistant TB strains, new
Organization (WHO) has declared as a worldwide catastrophe due drugs are immediately required and thus efforts have been twisted
506 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544
towards natural sources to finding of new TB leads. The bioactive
moiety from natural origin and their derivatives have been
described to display significant inhibition of the causative agent
and few of them have been selected as lead molecules for the
development of new mechanisms based antitubercular drugs
[2,23,24]. It's pre-requisite to mention here that compounds can be
classified as strong, weak and of middle class based on their min-
imum inhibitory concentrations (MICs) values, i.e. considered as
good with an MIC value of < 10 mg/mL or moderate up to 50 mg/mL,
respectively [25]. The antitubercular medicinal preparations have
been classified in different ways and as they exhibit different
mechanisms of action and also adept of exerting adverse effects on
a human body. There has been an immense improvement in new
methods to evaluate the antimycobacterial potential of several
chemical entities, reported throughout the last few decades [26,27].
The control on the tuberculosis has been extremely dependent
on the resistance developed by M. tuberculosis against the short
term antimycobacterial agents. Hence, a tough approach is required
to abolish these drug resistant pathogens by the discovery of novel
scaffolds as potent antitubercular candidates that can acts through
novel mechanism of action with minimum or no cross resistance
[28]. Despite the engagement of academic institutions and efforts
of the scientists from many pharmaceutical companies in the
development of antitubercular programmes, the current TB therapy
is static and weak [29]. The search for new antitubercular metab-
olites from natural sources still represents a great challenge for
researchers in spite of their rising efforts to determine effective
antitubercular molecules of plant origin [30]. Moreover, many sci-
entists have become attentive in the search for new leads from
micro-organisms such as fungi, yeasts, and bacteria [31e33]. In this
context, the search for new chemical entities (NCE's) from natural
sources to combat tuberculosis is high priority objective. Therefore,
in the extension of our review on bioactive alkaloids against
tuberculosis from natural origin [3], we compiled the antituber-
cular alkaloids up to date from natural sources. This review covers
the alkaloids with significant antimycobacterial activity and their
synthetic analogues possessing the same activity. Diverse alkaloids
amongst others phytochemicals have been presented on the basis
of their chemical class type. The chemical structure of compounds
with their minimum inhibitory concentrations, molecular targets
for comparing the effectiveness were mentioned also along with
special attentive glimpses of clinical manifestations, pathogenesis,
resistant types, different assay and diagnostics tools for tubercu-
losis. This review also highlighted the existing therapies for TB and
novel leads in pipeline, which includes pre-clinical and clinical
phase-I, II, III molecules. Furthermore, why phytochemicals lead
over the synthetic compounds considered for the possible treat-
ment and prophylaxis of tuberculosis along with molecular targets
for antimycobacterial agents have also been described.
2. Clinical manifestations and pathogenesis of tuberculosis
2.1. Clinical manifestations of tuberculosis
The clinical appearances of tuberculosis mainly defined as the
primary TB and secondary (reactivation) TB. Primary TB basically
considered as the disease of childhood with new TB infections
whereas the secondary TB designated as multiple terms like
chronic TB, recrudescent TB, endogenous reinfection, and adult-
type progressive TB. There are some other manifestations related
to especially pulmonary TB which includes Laryngeal TB, Lower
lung field TB and Tuberculoma.
Pulmonary TB is characterized by the sputum production, night
sweats, chronic cough, anorexia and hemoptysis [34]. About 45% of
patients suffer from extra-pulmonary tuberculosis and it varies
based on ethnic background, age, race and immunity [35]. HIV
contamination poses precise challenges to clinical administration
in patients with active tuberculosis. The threat of tuberculosis rises
quickly after contamination with HIV, and the symptoms of pul-
monary tuberculosis at this stage are just like those in HIV negative
patients [36]. In patients with cluster of differentiation-4 (CD4)
counts below 200 mm3, tuberculosis was manifested by atypical
infiltrates, hilar lymphodenopathy and pleural effusion whereas
patients having CD4 count less than 75 mm3 indicated with non
specific chronic febrile disease, mycobacteremia and multiple or-
gan involvement [36]. This type of condition led to misinterpreta-
tion of other diseases and later described after post mortem [37].
In endemic regions 10% tuberculosis cases are sub-clinical
tuberculosis or aymptomatic with negative sputum result, X-ray
and associated with HIV infections [34,38,39]. Around 25e30%
patient with HIV treatment are never diagnosed for tuberculosis
[40]. Therefore, intense screening for tuberculosis is suggested in
endemic region to highlight the patient with HIV associated
tuberculosis or non-communicable diseases such as diabetes or
chronic lung diseases [41,42].
2.2. Pathogenesis of tuberculosis
The infection by pathogenic strains of tuberculosis occurs
mainly in the oxygen-rich macrophages of the lungs. M. tuberculosis
infection happens when few air-dispersed tubercle bacilli from the
sufferer with active pulmonary tuberculosis reach the alveoli of the
host. Here, Mycobacterium is quickly phagocytized through alveolar
macrophages that can kill the entering bacteria due to the innate
immune response (Fig. 1) [43]. If, infection persists, bacilli start
replicating in macrophages and dispersed to epithelial and endo-
thelial cells. Due to exponential growth of Mycobacteria in few
weeks, it spreads to other organs through lymph and blood which
affects other cells as well [44,45]. Toll like receptors (TLR) mediated
production of cytokines and other chemical mediators act as signal
for mycobacterial infection and pathogenesis [46]. This results in
movement of monocytes associated macrophages and dendritic
cells to infection site in lungs. There, itself dendritic cells engulf
bacilli and migrate to lymph nodes to present Mycobacterium an-
tigens to CD4 and CD8 T-cells, which functionally activate these
cells [47e49]. Many studies established the involvement of CD4þ T-
cells against M. Tb protection, the evidence is reinforced by the
depletion of CD4þ T-cells, which is accountable for recurrence of
M. Tb in HIV-infected persons. There are different subsets of CD4þ
cells like T-helpers and regulatory T cells, which are co-operate or
hinder with each other to regulate infection. Developed T-cells
Fig. 1. Pathogenetic steps of M. tuberculosis.
 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544
proliferates and migrate back to the focal point of illness within the
lungs, in response to mediators produced by infected cells. These
episodes of cell migration in the direction of the infection focus
reach a pinnacle within the formation of granuloma, which is
hallmark of tuberculosis. This granuloma formation supports bacilli
dormancy for long time and prevents its disruption within mac-
rophages. Dormant bacilli housed within granuloma can released
during favorable conditions and triggers relapsing of infection.
Entry of Mycobacteria into macrophages occurred through choles-
terol domains of plasma membrane that was mediated by binding
to receptor and phagocytosis [50]. In vitro studies elucidated the
role of different receptor, which involve Mycobacterium uptake by
macrophages whereas in vivo studies nullify the evidence in sup-
port of in vitro studies [51e53]. The in vivo Mycobacteria uptake
involves various other receptors such as complement receptors,
scavenger receptor and C-type lectin receptors.
Nearly all of the in vitro experiences point out that the bacilli
favour interplay with complement and mannose receptors, which
are benign, because they set off minimal superoxide production. In
distinction, Mycobacteria uptake by Fc (fragment crystallizable)
receptors, which play a minor function in the absence of exact
antibodies, set off a vigorous host response and set up an exact
intracellular trafficking pathway [54]. This is the reason for pre-
venting internalization of receptors by Mycobacteria and depicts
the little effect of receptor on its survival [55,56].
3. Existing therapies and tools to combat tuberculosis
Current therapy uses more than one drug, which involves two
principles. First, to prevent development of drug resistance and
second, to strengthen drugs potency. The available drugs are
sometimes moderately effective due to the impermeable nature of
the Mycobacterium cell wall and the inclination of M. tuberculosis to
develop resistance to current TB therapies [57]. Responsible bac-
teria generate resistance to drugs because their chromosome un-
dergoes random mutation. Positively, these chromosomal
mutations are unlinked in terms of either location or function.
Moreover, selectivity to a particular drug or its class, unplanned
genesis of a species with multi-resistance, is particularly implau-
sible. Faulty regimen always leads to acquire drug resistance [40].
Sometimes the treatment comprises more than four drugs for
up to 18 months if the strain is resistant to multiple antibiotic forms
and if treatment fails due to drug resistance than surgery is
essential to eliminate infected tissue. Moreover, the patients asso-
ciated with AIDS raise one more difficulty, which occurs with the
routine treatment is the apparent of drug-drug interactions, likely
between rifampin and other anti-retroviral drugs used for the cure
of AIDS [58]. Several drugs have been passed in the clinical trials
and are being used in various stages in different combination and in
different conditions depending upon the new and drug resistant
patients. Isoniazid, Rifampicin, Pyrazinamide, Ethambutol and
Streptomycin are the five primary or first line TB drugs along with
attentive spotlight on the second line, third line and the pipeline
drugs for the treatment of tuberculosis are depicted with their
structures (Fig. 2aed). These are Group 1 drugs except strepto-
mycin, which comes in Group 2 with other injectables. Group 2 to 5
is termed as second line TB drugs. Drugs in fifth group are not
commonly used; they are prescribed only when others fail
[40,59,60].
3.1. Pioneer drugs in the treatment of tuberculosis
Since 1952, first line antimycobacterial drugs are the standard
regimen to initiate the treatment for tuberculosis. These drugs are
the first one which are clinically used and found to be effective at
507
that time. Later on, due to emergence of resistance to these first line
therapies, the Centre for Diseases Control (CDC) and World Health
Organization (WHO) launched the new class of drugs designated as
second and third line drugs for the resistant tuberculosis.
Isoniazid (INH, 1) is chemically known as pyridine-4-carboxy
hydrazide and was firstly synthesized in 1912, but clinically
approved as antimycobacterial drugs in 1952. INH cured many
patients in New York hospital and recognized as a ‘magic drug’ [61].
INH discovery lead a milestone and addition of new molecule in
antitubercular armamentarium. INH contains hydrazide and pyri-
dine group, which is essential for antimycobacterial activity [62]. As
a prodrug, INH transformed into INH-NAD conjugation with the
assistance of M. Tb catalase-peroxidase kat G enzyme that inhibits
the mycolic acid biosynthesis of M. Tb [63]. The inhibition of enoyl-
ACP reductase (encoded by inhA gene) causes an accumulation of
long-chain fatty acids and cell death. Mutation in katG315 and inhA
enzyme is the major cause of emergence of resistance to INH [63].
Kat G mutation in Mycobacteria was compensated by over expres-
sion of the ahpC gene [64,65]. Mutation in NADH dehydrogenase
encoding gene ndh develops resistance of INH in M. bovis [66]. INH
resistance due to another 16 genes mutation is also reported apart
from their known mechanism of resistance [67].
Ethambutol (EMB, 2) was introduced in 1961 and chemically it is
dextro-(2,2-ethylenediamino)-di-1-butanol. It has proven that S, S
isomer of EMB is 600 times active than other stereoisomers. It's
mode of action have different sites including phospholipid syn-
thesis, RNA metabolism, and mycolic acid transfer [68]. Resistance
to ethambutol was found to be linked to mutation in embCAB gene,
which encodes molecular targets for ethambutol [69].
Pyrazinamide (PZA, 3) was firstly synthesized in 1936 by Dalmar
et al. and introduced in 1952 as antimycobacterial drugs. Pyr-
azinamide is first line of drug in treatment of antimycobacterial
agents and in addition, with rifamycin analogues, it kills tubercle
bacilli and reduces the treatment regimen from 9 months to 6
months. As pyrazinamide is prodrug, it is converted into pyrazinoic
acid where it transformed in protonated pyrazinoic acid, which
inhibits bacterial cell and membrane transport breakage [70].
Resistance to pyrazinamide was due to mis-sense mutation in pncA
gene that leads to amino acid substitutions [71e73].
Rifamycin derivatives (RMP; 4, 5, and 6) were the most potent
drugs used for the treatment of tuberculosis and were reported by
Lepetit Research Laboratory, Italy [74]. They consist of aromatic ring
with aliphatic bridge on both sides. The substitution on rifamycin at
C-1, C-8, C-21 or C-23 usually results in decrease in anti-
mycobacterial activity. Rifamycin has three derivatives used as
antitubercular viz. Rifampicin, rifabutin, rifapentine. Rifampicin
also called, as rifampin, is a 3-formyl derivative; rifabutin is spi-
ropiperidyl derivative whereas rifapentine is cyclopentyl derivative
of rifampin. Rifamycin is most potent bactericidal and sterilizing
chemotherapeutics in tuberculosis although its effect is lower
when compared to INH in first two days of initiation of treatment
[75,76]. Rifamycin analogues inhibit the DNA dependent RNA po-
lymerase, which catalyzes the polymerization of chain. Mutation in
rpoB gene that encodes for RNA polymerase beta subunit developed
the resistance to rifamycin derivatives. In rifampin, there is rifam-
picin resistant determining region which carries 507 codons
through 533 of the rpoB gene [77e79].
A drug may be classed as second-line instead of first-line if it
may be less effective than the first-line drugs (e.g., p-aminosalicylic
acid); or, it may have toxic side-effects (e.g., cycloserine); or it may
be effective, but unavailable in many developing countries (e.g.,
fluoroquinolones). Streptomycin (SM, 7) is a derivative of amino-
cyclitol glycoside antibiotic. It directly inhibits protein synthesis by
misreading in genetic code and initiation in translation of mRNA
[80,81]. Mutation in rpsL gene, which encodes ribosomal protein
508 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544
Fig. 2. a: Chemical structure of First line Antitubercular drugs.
b: Chemical structure of Second Line Antitubercular drugs.
c: Chemical structure of Third line Antitubercular drugs.
d: Structure of Pipeline drugs for the treatment of tuberculosis.
leads to streptomycin resistance to M. Tb [82,83]. The representa-
tive example of second line drugs include aminoglycosides (e.g.,
streptomycin 7, amikacin 8, kanamycin 9), polypeptides (e.g., cap-
reomycin 10, viomycin 11) fluoroquinolones (e.g., levofloxacin 12,
moxifloxacin 13, gatifloxacin 14, ciprofloxacin 15, and ofloxacin 16),
p-aminosalicylic acid 17, D-cycloserine 18 and less-effective second-
line antituberculosis drugs like thioamides (e.g. ethionamide 19
and prothionamide 20), terizidone 21. These are only used to treat
tuberculosis that is resistant to first line therapy i.e., for extensively
drug-resistant tuberculosis (XDR-TB) or multidrug-resistant
tuberculosis (MDR-TB) [1,2].
Third-line drugs (22-34) include the entities that may be useful,
but have unproven or doubtful efficacy such as rifabutin, clari-
thromycin, linezolid, thioacetazone, thioridazine, bedaquiline, etc
(Fig. 2c). Thus, the third-line drugs are either not very effective (e.g.,
clarithromycin) or their efficacy has not been proven yet (e.g.,
linezolid, R207910). Rifabutin is although found to be effective, but
is not included in WHO list for most developing countries mainly
because of its pharmaco economic factor [1].
In addition to these classes of antitubercolosis drugs, the pipe-
line drugs (35-46) for the possible treatment of tuberculosis are
depicted in Fig. 2d. Existing drug and new chemical entities having
promising antitubercular activities with their mode of action are
depicted in Table 1 [84e124].
4. Resistance to current antimycobacterial agents
The toxicity and serious side effects of second line drugs despite
their limited use for the treatment of MDR-TB and XDR-TB, the most
M. Tb resistance is attributed to the spontaneous mutation to the
targeted protein that interfere the binding site of used drugs [125].
Drug resistant TB is defined as the condition whentuberculosis
infection does not respond or resistant to one or more of anti-
mycobacterial drugs. Resistance may develop due to so many fac-
tors such as failure to follow TB regimen or inadequate TB
treatment or improper diagnosis. Another important point which
indicates for the development of resistant TB was transmission of
resistant strain of tuberculosis from one person to another [126]. As
per WHO survey, India, China and Russia are the prominent having
the cases of resistant TB (MDR/XDR) comprises 45% of total world's
population [127].
4.1. Multi drug resistance tuberculosis (MDR-TB)
Worldwide WHO survey reports shows 10% TB cases out of
7,00,000 treated with high quality regimen and this regimen was
based on individualized in vitro drug susceptibility test [128]. MDR-
TB was characterized by resistance of Mycobacteria to isoniazid and
rifampicin, commonly used regimen for tuberculosis [129]. MDR-TB
was less responsive to six-month regimen and clinicians move the
regimen for two or more years with more expensive drugs
[130,131]. Xpert M. Tb/RIF assay is a diagnostic tool used for diag-
nosis of tuberculosis and rifampicin resistance within 2 h of test
[132,133]. Currently, MDR-TB was treated with four second-line of
antimycobacterial drugs under the supervision of DOT program and
the total duration of treatment is 20e24 months in case of no
history of MDR-TB and 28e30 months for previously detected
MDR-TB.
4.2. Extensively drug resistant tuberculosis (XDR-TB)
Extensively drug resistant tuberculosis is defined as resistance
developed by Mycobacteria for isoniazid, rifampicin, fluo-
roquinolones and amikacin or kanamycin or capreomycin inject-
ables [134]. In some cases; treatment of XDR-TB involves third line
of antimycobacterial drugs that has more side effects and cost of
treatment.
4.3. Totally drug resistant tuberculosis (TDR-TB)
This is also known as Extremly Drug Resistant Tuberculosis
(XXDR-TB), which is resistant to all first line as well as all second
 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544 509

Fig. 2. (continued).

line drugs. After first resistance report in 2007, the increasing rate
of resistant tuberculosis i.e. (MDR-TB; XDR-TB) leads to new form of
total drug resistant tuberculosis, which is a major concern for
public health as it indicates towards regimen failure [135].
5. Novel antituberculosis drugs in pipeline
From last few years, there is an increase in drug discovery and
development of antimycobacterial agents. There is number of lead
molecules for optimization, preclinical, and clinical trials (phase-II
and III trials) but in phase-I trial, loopholes needs to be filled for
proper screening of molecules and further advancement [136]. Ef-
fect of existing antitubercular drugs on tubercle bacilli and
physiological changes in tubercle bacilli are depicted in Fig. 3.
Quinolone derivatives such as fluoroquinolones now-a-days are
the established scaffold for various bacterial infections and suc-
cessfully included in regimen but there is still a need to refurbish
these moieties for development of antitubercular drugs for resis-
tant strains [137,138].
New imidazooxazole derivatives Delamanid (OPC67683) and
pretomanid-moxifloxacin-pyrazinamide (PA-824) are in phase-III
trial and their metabolism from prodrug to active drug depends
on F420-dezazaflavin-dependent nitroreductase found in Myco-
bacteria. Des-nitroimidazole molecule generates nitric oxide that
leads to inhibition of anaerobic activity [139,140]. PA-824 was
effective against both active and latent tubercular infection and
510 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544
Fig. 2. (continued).
reduces the period of regimen [141]. Delamanid acts by inhibiting
mycolic acid synthesis and increased sputum production in resis-
tant tuberculosis [142,143]. In combination with other anti-
mycobacterial agents delamanid has shown its effectiveness with
acceptable toxicity [144].
SQ-109 is under clinical phase-II trial and found active against
both MDR-TB and XDR-TB (Fig. 4) [145,146]. Chemically, it is 1,2-
ethylenediamine {N-(2-adamantyl)-N-[(2E)-3,7 dimethyl octa-2,6-
dienyl] ethane-1,2-diamine} found after the screening of around
63,000 entities having skeleton similar to ethambutol (1,2-
ethylenediamine). SQ-109 is lead molecule for trials after
screening to search new molecule for TB with more efficacy and
low toxicity.
Its pharmacological parameters were found different when
compared to ethambutol as it targets MmpL3 transporter system,
which enables movement of trehalose monomycolate into bacterial
cell wall, and interfere with synthesis of mycolic acid [147]. Urea
derivatives were in lead optimization stage, which also targets
MmpL3 transporter and appear a novel target for antimycobacterial
discovery and development.
Rifamycin analogue named Rifapentine is more potent than
rifampicin and acts by binding to RNA polymerase (b-subunit) in
Mycobacteria [148]. In vitro and in vivo studies of rifapentine against
M. tuberculosis reported MIC 0.02e0.06 mg/mL [149]. Clinically
rifapentine was used with isoniazid once weekly against latent
tuberculosis for 3 months and 2 months for active tuberculosis at
the dose of 600 mg twice weekly in intensive regimen and once
weekly for maintenance phase as approved by USFDA [150,151].
Inhalational dosage in animals produced a good result as tubercle
clearance is better and orally it might cure active as well as latent
tuberculosis within 3 months. Clinical trial based on these pre-
clinical data was not satisfactory and hence needs more concern
[152].
Since last four decades, there is no affirmative result in the field
of antimycobacterial drug discovery. However, in 2012 USFDA
approved a new quinoline analogue Bedaquiline (TMC-207) for the
cure of MDR-TB and now days it is in phase-III trials of drug
approval. It inhibits ATP synthase in active and dormant stage of
Mycobacteria. Human mitochondrial ATP synthase has 20,000 fold
less sensitive compared to Mycobacteria ATP synthase to diary-
lquinoline, therefore this target is important for future implications
of antimycobacterial agents [153]. During drug discovery, scientist
analyzed whole genome of M. tuberculosis and M. smegmatis to find
mutant gene for resistance development and hence found atpE
gene encodes for ATP synthase [154,155]. QT prolongation is
noticed adverse effect of bedaquiline but it effects against MDR-TB,
XDR-TB and TDR-TB leads to a new addition of armor in anti-
mycobacterial class [155].
Another semisynthetic arrangement of spectinomycin ana-
logues (47) (Fig. 5) with particular ribosomal restraint and slender
 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544 511

O N
F O H
O N N NO2
O N
N N O
N N H
O
HO OH F O
F3CO
35(AZD 5847) 36 (SQ 109) 37 (TBA 354)

O O HO
F COOH
HN
H2 N N N N N
O N
OMe F
HO OH NH2
O O
HO OH
HO OH 39 (DC 159a) 41 (SQ 609) O
O O O
O O
N O O
N H Cl NH
N N O NH2
H N N O
N O O
O O
C4H9 N OCF3 N HN
O H
38 (CPZEN 45) 40 (Q 203) 42 (SQ 641)

OCF3 OMe O
O O
NO2 S NH
O
NO2 N S N
S N O
N N N S
F3C NH
N
F3C O N
N O
N N O
H
OMe
43 (TBI 166) 44 (PBTZ 169) 45 (BTZ 043) 46 (TCA 1)

Fig. 2. (continued).

range antitubercular action had been produced [156]. On various
murine infectious models, these spectinamides were all around
endured, essentially diminished lung mycobacterial load and
expanded survival. Further studies suggested lack of cross resis-
tance with existing antimycobacterial activity against multi-drug
resistant (MDR) and extensively drug resistant tuberculosis (XDR).
Their powerful hostile to tubercular properties is the basic alter-
ation to avoid the Rv1258c efflux pump, which is controlled in MDR
strains and is embroiled in macrophage actuated drug resilience.
Synthetic changes to antimicrobial drugs results in newer treat-
ment against intrinsic pump mediated resistance and led to explore
pathway of the drug discovery and development for tuberculosis
[156].
BTZ043 (45) is chemically known as 2-[(2S) 2-methyl-1,4-dioxa-
8-azaspiro[4.5]dec-8-yl]-8-nitro-6-trifluoromethyl-4-H-1,3-
benzothiazin-4-one which efficiently prevents the M. Tb cell wall
synthesis by inhibiting the DprE1, essential for the synthesis of D-
arabinofuranose, a part of arabinogalactan and arabinomannan
[157]. BTZ043 shows its potency against all M. Tb strains especially
to clinical isolates from MDR and XDR patients. An in vitro study
indicates MIC ranges between ~0.1e80 ng/mL and 1e30 ng/mL
against M. tuberculosis. In vivo study of BTZ043 shows superior
activity to isoniazid in mouse models for the duration of 2 months
or more. Further toxicological studies shows that, BTZ043 was non
toxic up to the dose of 180 mg/kg in rodents and have no action
with cytochrome enzymes or hERG channel. As per OECD
guidelines, genotoxicity, mutagenicity and carcinogenicity of
BTZ043 were also studied and implicate negative results proving its
stability as well as safety profile [157].
6. Common molecular targets for antimycobacterial agents
Antimycobacterial agents have bactericidal as well as bacterio-
static properties. The former one inhibits the M.TB, whereas the
later one averts the growth of M.TB. Various molecular targets are
well-known for the individual existing antitubercular drugs. The
targets decided for novel lead identification is specific to avert
transfer of mutated gene from one generation to another. The novel
molecule should active against throughout the lifecycle of M.TB
[158]. Inside and outside of mammalian cells; different biosynthetic
pathway was included for antitubercular drugs viz. interruption of
bacterial protein synthesis, cell wall synthesis and nucleic acid
synthesis (Fig. 6). Drug discovery and development of lead mole-
cule focused on specific targets, which include both classes i.e.
bactericidal and bacteriostatic. Lots of research was going on but
until date, no natural lead was discovered with safety and potency
profile. Apart from these, we are enlisting various molecular targets
for antimycobacterial agents [159].
6.1. Protein synthesis
Generally, antimycobacterial leads target protein synthesis as it
512 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544

Table 1
List of existing and pipeline drugs useful for the treatment of tuberculosis.

S Drug Origin Chemical Class MIC (mg/mL) Mechanism of action Target gene involved
No.

First Line of Antitubercular Drugs (Orally)

1. Isoniazid (1) Synthetic Isonicotinic acid analogue 0.01e0.20 mg/mL Inhibits mycolic acid synthesis, affect DNA, lipids katG, inhA, ndh [84]
and carbohydrates
2. Ethambutol (2) Synthetic Amino-alcohol derivative 1-5 mg/mL Arabinogalactanbiosynhesis inhibition embCAB [84]
3. Pyrazinamide (3) Synthetic Pyrazinecarboxamide 20-100 mg/mL Targets membrane energy metabolism; pncA [85]
derivative membrane transport breakage
4. Rifampicin (4) Natural/ Rifamycin derivative 0.05e0.50 (0.486) RNA synthesis inhibition, target NA polymerase rpoB [84]
Semi mg/mL b sub unit
synthetic
5. Rifabutin (5) Semi Ansamycin derivative 0.015e0.125 mg/ RNA synthesis rpoB (Rv0667) [86]
synthetic mL
6. Rifapentine (6) Semi Rifamycin derivative 0.03e0.06 mg/mL RNA synthesis rpoB(Rv0667) [86]
synthetic
Second Line of Antitubercular Drugs
Injectables Aminoglycosides
7. Streptomycin (7) Natural Aminoglycosides analogues 2e8 mg/mL S12 and 16S rRNA components rpsL, rrs [84]
of 30S ribosomal subunit
8. Amikacin (8) Semi Aminoglycoside derivative 0.12e0.25 mg/mL Protein synthesis rrs (M.Tb 000019) [87]
synthetic
9. Kanamycin (9) Natural Aminoglycosides 1-2 mg/mL Inhibition of protein synthesis rrs (16SrRNA) [88]
Injectables Polypeptides
10. Capreomycin (10) Natural Aminoglycosides 1.25e2.25 mg/mL Inhibition of protein synthesis (rrs) 16SrRNA, 50S ribosome,
rRNAmethyltransferase
(TlyA) [89]
11. Viomycin (11) Synthetic Tuberactinomycins 4-8 mg/mL Inhibition of protein synthesis vph (70S tRNA) [89]
Oral and injectable fluoroquinolones
12. Levofloxacin (12) Synthetic Ofloxacin L-isomer 0.5e0.75 mg/mL DNA replication and transcription gyrB (Rv0005); gyrA (Rv0006)
[90]
13. Moxifloxacin (13) Synthetic Quinolone analogue 1.0 mg/mL DNA replication and transcription gyrB(Rv0005); gyrA(Rv0006).
[91,92]
14. Gatifloxacin (14) Synthetic Fluoroquinolone derivative 1.0 mg/mL DNA replication and transcription gyrB(Rv0005); gyrA(Rv0006)
[91,93]
15. Ciprofloxacin (15) Synthetic Fluoroquinolone analogue 0.125e2 mg/mL DNA replication and transcription gyrB(Rv0005); gyrA(Rv0006)
[91,94]
16. Ofloxacin (16) Synthetic Fluoroquinolone analogue 0.125e2 mg/mL DNA replication and transcription gyrB(Rv0005); gyrA(Rv0006)
[91,94]
Oral Second line drugs
16. Para amino salicylic Synthetic Para aminobenzoic acid 1-8 mg/mL Inhibition of folate pathway and mycobactin thyA(Thymidylate synthase)
acid (17) derivative genesis [95]
17. D-Cycloserine (18) Natural Amino acid derivative 1.2e8 mg/mL D-Alanine metabolism alr(Rv3423c); ddlA(Rv2981c)
[96,97]
18. Ethionamide (19) Synthetic Nicotinamide derivative 0.6e2.5 mg/mL Inhibition of mycolic acid synthesis inhA(Acyl carrier protein
reductase) [84]
19. Prothionamide (20) Synthetic Thiomide derivative 0.3e1.2 mg/mL Cell wall inhA(Rv1484) [98]
20. Terizidone (21) Synthetic Analogue of cycloserine 8-32 mg/mL Peptidoglycan synthesis alr (Rv3423c); ddlA (Rv2981c)
[99]
21. Thioacetazone (30) Synthetic Thio-semicarbazone 0.1 mg/mL Cell wall cmaA2(Rv0503c) [100]
22. Linezolid (31) Synthetic Oxazolidienone analogue 0.5 mg/mL Protein synthesis rplC(Rv0701) [101,102]
Third Line Antitubercular Drugs (MDR/XDR)
23. Meropenem (22) and Semi Carbapenem derivative 0.5 mg/mL & 0.23 Peptidoglycan Synthesis pbpB(Rv2163c); blaC(Rv2068c)
Clavulanate (23) synthetic e0.84 mM [103]
24. Amoxicillin (24) and Semi Penicillin derivatives 10 mg/mL & 0.23 Peptidoglycan synthesis ponA1 (Rv0050); blaC
Clavulanate (23) synthetic e0.84 mM (Rv2068c) [104]
25. Imipenem Semi- Thienamycin analogue 0.16 mg/mL Peptidoglycan synthesis pbpB, ftsI (Rv2163c) [105]
and Cilastatin (25, 27) synthetic
26. Clarithromycin (26) Semi Macrolide analogue 1 mg/mL Protein synthesis rplV (Rv0706) [106]
synthetic
27. Clofazimine (28) Synthetic Riminophenazine analogue 0.12e0.24 mg/mL Probably membrane transport. rv0678 [107]
28. Bedaquiline (29) Synthetic Diarylquinoline analogue 0.063 mg/mL Oxidative phosphorylation atpE (Rv1305) [108]
29. Pretomanid (32) Synthetic Nitroimidazole analogue 0.015e0.25 mg/mL Probably targeting cell wall, and Target gene is not yet known
causing respiratory poisoning [109]
30. Sutezolid (33) Synthetic Oxazolidienone analogue 0.5e4 mg/mL Protein synthesis rplC(Rv0701) [110,111]
31. Delamanid (34) Synthetic Dihydro-nitroimidazo- 0.006e0.024 mg/ Inhibiting mycolic acid synthesis Rv3547 [112]
oxazole derivative mL
Antitubercular drugs in pipeline
32. AZD-5847 (35) Synthetic Oxazolidienone analogue 0.25e1.0 mg/mL Protein synthesis rplC(Rv0701) [113]
33. SQ109 (36) Synthetic 1,2-ethylenediamine 0.78 mg/mL Cell wall mmpl3(Rv0206c) [114]
34. TBA-354 (37) Synthetic Nitroimidazole derivative 0.34 mg/mL Probably inhibiting cell wall Target gene is not yet known
synthesis, and causing respiratory [115]
poisoning
35. CPZEN-45 (38) Natural/ Caprazamycin analogue 1.56 mg/mL Cell wall wecA, rfe (Rv1302) [116]
Semi
synthetic
 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544 513

Table 1 (continued )

S Drug Origin Chemical Class MIC (mg/mL) Mechanism of action Target gene involved
No.

36. DC-159a (39) Synthetic Fluroquinolones derivative 0.5 mg/mL DNA replication and transcription gyrB(Rv0005); gyrA(Rv0006)
[117]
37. Q203 (40) Synthetic Imidazopyridine amide 2.7 nM Oxidative phosphorylation qcrB(Rv2196) [118]
38. SQ609 (41) Synthetic Dipiperidine analogue 4 mg/mL Probably cell wall biosynthesis Target gene is not yet known
[119]
39. SQ641 (42) Synthetic Capreomycin analogue 0.12e0.28 mg/mL Cell wall mraY(Rv2156c) [120]
40. TBI-166 (43) Synthetic Clofazimine analogue 0.016 mg/mL Membrane transport Target gene is not yet known
[121]
41. PBTZ-169 (44) Synthetic Piperazinobenzothiazinone 0.0003 mg/mL Inhibits DprE1, an enzyme essential for the DprE1(Rv3790) [122]
derivative biosynthesis of key cell wall components
42. BTZ043 (45) Synthetic Piperazinobenzothiazinone 0.001 mg/mL Inhibits DprE1, an enzyme essential for the DprE1(Rv3790) [122]
derivative biosynthesis of key cell wall components
43. TCA-1 (46) Synthetic Benzothiazone analogue 0.01e0.19 mg/mL Inhibits DprE1, an enzyme essential for the DprE1(Rv3790), katG, fdxA
(biofilm media) biosynthesis of key cell wall components [123,124]

involves RNA and DNA, the nuclear elements [160,161]. Many
existing drugs such as chloramphenicol, tetracyclines and others
are potent inhibitor of protein synthesis but lack antitubercular
activity. Streptomycin, aminoglycoside analogue inhibits protein
synthesis and disrupts their metabolism [162,163].
6.2. Nucleic acids biosynthesis and DNA gyrase
6.3. Nucleotide biosynthesis
Nucleotide biosynthesis is an important link for discovery of
new antitubercular drugs especially TB in HIV cases. Thymidine
monophosphate kinase (dTMKase) has been indicated as molecular
target to develop novel antimycobacterial drugs for TB in HIV cases,
MDR-TB, XDR-TB [169,170]. dTMKase catalyzes phosphorylation of
thymidine monophoshate (dTMP) to thymidine diphosphate
(dTDP) which is also target of anti-HIV agent [171].

Tetrahydrofolate reductase is an enzyme involved in folic acid
synthesis, which is a rational target for antitubercular drugs. PAS,
sulphonamides inhibits tetrahydrofolate biosynthesis and block the
synthesis of purine and pyrimidine, which is essential component
of nucleic acid synthesis.
DNA gyrase is also a target enzyme for antimycobacterial leads
as it was involved in negative supercoiling of dsDNA and it keen
interest of researcher for novel molecule discovery [164e166].
Fluoroquinolones such as moxifloxacin, gatifloxacin are the in-
hibitor of DNA gyrase and exist as good antitubercular drugs in
combination with other TB drugs [167,168].
Fig. 3. Effect of antitubercular drugs on tubercle bacilli and physiological changes in
tubercle bacilli.
6.4. Cell wall macromolecule biosynthesis
The virulence of M. Tb is due to its cell wall, which is made up
lipophilic mycolic acid, arabinogalactan, peptidoglycan and they are
known to prevent entry of dyes and stains. Cell wall helps M. Tb to
maintain its viability during adverse conditions. Hence, cell wall
synthesis is a molecular target to kill the bacteria as enzymes
involved in the biosynthesis are pathogen specific and they do not
have homologues in the mammalian system [172e174].
Recently, Xin-Shan Ye Research Group reported a really chal-
lenging synthesis of an arabinogalactan (that contains 92 sugars),
which is an essential cell-wall component in M. tuberculosis and is
responsible to causes tuberculosis [175]. Ethambutol works by
blocking the polysaccharide's biosynthesis (Arabnosyl Transferase).
This may lead to a novel tuberculosis vaccines and help a better
understanding of the bacterium's mechanism of cell-wall biosyn-
thesis for the drug development against tuberculosis.
Furthermore, several sugar-based promising molecules having
necessary structural features as possible inhibitors of the Myco-
bacterial cell wall biosynthesis has been developed through the
extensive research contributed by Tripathi Group [176]. Based on
promising antitubercular activities associated with D-cycloserine, a
cyclic analogue of alanine known to inhibit enzymes alanine race-
mase and alanine synthatase involved in peptidoglycan biosyn-
thesis, a series of glycosylated b-amino ester derived from D-
glucose was developed, where one compound bearing long alkyl
chain at amino group has shown promising activities against
Mycobacterium tuberculosis, M. avium, M. fortuitum and M. smeg-
matis (upto MIC 3.12 mg/mL) [177]. Mechanisms of action invisaged
to be the similar to D-cycloserine and also believe to reduce the
toxicity as well improve the pharmacokinetic parameter by intro-
ducing the suitably protected glycogyl residue to the amino acid
skeleton.
Keeping in view the structure of ethambutol for targeting the
inhibition of arabinosyl transferase involved in cell wall
514 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544
Fig. 4. Pipeline drugs for tuberculosis.
biosynthesis, a series of potent glycosyl amino alcohols [178,179]
and N1, Nn-bis-glycosylated diamino alcohols [180] were reported
by Tripathi et al., where few of them exhibited anti-TB activity with
MIC 6.25e3.12 mg/mL in virulent and avirulent strains. These
compounds were designed to mimic the enzyme D-alanine race-
mase and glycosyl transferase involved in the biosynthesis of
essential cell wall peptidoglycan and arabinogalactan. Few phenyl
cyclopropyl methanones exhibit promising anti-TB activities
against M. tuberculosis H37Rv (MIC upto 3.125 mg/mL), where the
most active one showed activity against MDR strains [181]. From a
series of galactopyranosyl amino alcohols, a N1,Nn-bis-galactopyr-
anosyl amino alcohol showed potent activity against M. tubercu-
losis H37Rv in vitro and also displayed activity in MDR TB [182]. The
compound was found to be superior to ethambutol clinically used
anti TB drug in in vitro screening.
6.5. Fatty acid biosynthesis
Mycolic acid is important components of M. Tb cell wall. Initial
precursor of mycolic acid synthesis leads to molecular targets for
novel antimycobacterial drugs. M. tuberculosis has type-I and type-
II of fatty acid synthase (FAS-I and FAS-II respectively) pathways. In
Fig. 5. Spectinomycin analogues.
FAS-I, C16eC26 fatty acids are synthesized, whereas in FAS-II these
fatty acid chains are lengthened up to C56, which serves as pre-
cursors for mycolic acids [183]. FAS-I configuration is similar to
mammalian system while FAS-II system is distinct to microbes.
Mycocerosic acids are branched fatty acid generated from methyl
malonyl-CoA, found in the cell wall of the M. Tb. The synthesis of
the precursor methyl malonyl-CoA becomes a potential drug mo-
lecular target [184].
Thus, in the alarming circumstance of the emergence of MDR,
EDR, and TDR tuberculosis, understanding of the biosynthesis of
mycolic acids, a specific and major lipid component of the myco-
bacterial cell envelope is an essential for the survival of members of
the genus Mycobacterium and is a critical determinant of the
mycobacterial physiology [185]. This may open an opportunity for
the development of mechanism based novel antimycobacterial
agents and considered as an important molecular target. Antitu-
bercular drug isoxyl and thioacetazone are well-known inhibitor of
mycolic acid biosynthesis in M. bovis during a 6-hr exposure to
10 mg/mL [186,187].
6.6. Isocitrate lyase
Isocitrate lyase (ICL) converts isocitrate into succinate during
glyoxalate shunt, which helps in growth of bacteria and plants by
using acetate and fatty acids. During study of M. Tb it is realized that
level of isocitrate lyase (ICL) increases abruptly when it infects
human macrophages [188e190]. The most noticeable point is that
ICL is not required for viability of tubercle bacilli in any conditions
either normal or hypoxic seen in M. Tb infected mice. ICL is required
for persistence and virulence of tubercle bacilli and icl gene en-
codes for this resistance to antimycobacterial agents [191]. icl-1 and
icl-2 deletion has marked effect on M. Tb infected mice and human
macrophages and inhibition of intracellular replication. ICL in-
hibitors could be recognized as the new possible targets for
tuberculosis.
 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544
Fig. 6. Molecular targets for antimycobacterial drugs [158].
6.7. ATP biosynthesis
ATP is essentially required for the proper functioning of bacterial
cell and it requires ATP synthase which is an essential enzyme in
the process by which M. tb generates energy in the form of ATP. For
the novel discovery and development of antimycobacterials a
possible target is ATP synthase which directly alter the pathway
and led to inhibition of bacterial cell.
Well-known antitubercular drug bedaquiline targets the ATP
synthase enzyme of the TB mycobacteria. Among ATP synthase
inhibitors a novel diarylquinoline R207910 inhibits M. tuberculosis
[192,193]. In addition to the discovery of novel drug targets, the
recent development in drug development against TB has also
received considerable attention in the area of antibiotic develop-
ment [193]. Recently, Andries et al. have made a promising new
development in the front of antibiotic development, and have
successfully identified a potent diarylquinoline, R207910 that in-
hibits both drug-sensitive and drug-resistant M. tuberculosis in vitro
with MIC 0.06 mg/mL [194].
Further more, glycosyl uriedes [195,196], amines and amino
alcohol [180], enaminones [197], and glycopeptide [198] reported
by Tripathi et al. after virtual screening program using the modeled
domain from MtuLigA with the potential to bind to this domain,
have shown to inhibit Mtu LigA with several fold specificity
compared to ATP-dependent ligases including for the human DNA
ligase I. Bacterial growth inhibition studies using specific LigA
deficient strains suggest that their observed antibacterial activity is
most likely due to inhibition of the LigA in the bacteria [199,200].
7. Assay and diagnostic tools for tuberculosis
7.1. Assays for tuberculosis
In order to establish appropriate linkage in drug discovery and
development, bioassays are the most significant steps. Several as-
says have been discussed against Mycobacterium sp.
7.1.1. In vivo assay for Mycobacterium
Virulent strain, M. tuberculosis H37Rv (ATCC 27294) is repre-
sentative strain for maximum clinical isolates to check drug
515
susceptibility profile. Another strain was also considered by the
researchers working on drug development against tuberculosis,
which is mainly due to its rapid growing capacity and saprophytic
nature. M. smegmatis (ATCC 607), M. tuberculosis H37Ra (ATCC
25177) and M. bovis BCG (ATCC 35743) was extensively used in
place of M. tuberculosis H37Rv for drug susceptibility investigation
[201].
Mice models are very common for in vivo assay in which aerosol
infection of susceptible strain Mycobacterium is given to mice.
Mycobacteria invades lung and divide for a long period to enter in
active phase and depending on experimental design, treatment
protocol was followed.
7.1.2. In vitro assay for Mycobacterium
Various in vitro assays were developed to investigate anti-
mycobacterial activity. Mycobacterium is cultured in broth, agar
based media, and it takes several weeks for growth. Non-virulent
species such as M. avium, M. intracellulare, M. kansasii, M. fortu-
itum, M. smegmatis were used for the in vitro assay.
7.1.2.1. Macro and micro agar dilution. Test compounds in agar
media are allowed for determining the MIC. Middelbrook 7H11 agar
media was used to culture Mycobacterium, which is supplemented
with albumin, dextrose, oleic acid and catalase [202]. Test samples
are cultured with media at 1% v/v and then 20 mL added to stan-
dard 150 mm diameter petri dishes, 4 mL to 6-well microplates or
1.5 mL to 24 well microplates. In case of 96 well plates 100e200 mL
medium is used for assay. At 37 C sample were incubated over-
night and plates can be inverted for the remainder of the incubation
period. This assay takes nearly 18e20 days to visualize growth of
the colonies.
7.1.2.2. Radiorespirometry. The growth or inhibition of Mycobac-
teria can be determined within seven days by the oxidation of
palmitic acid in Middelbrook 7H12 medium to 14CO2, which can be
measured in BACTEC 460 instrument [203,204]. Some non-
radiometric systems have also been developed where oxygen
consumption and CO2 production is determined to quantify the
growth inhibition by test compound [205e207].
516 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544

Table 2
Nucleic acid techniques enduring for the diagnosis of tuberculosis [229].

Technology Developed at Targets Amplification reaction Active features Status of product development

EasyNAT Ustar Biotechnologies IS6110 Cross priming Isothermal 65. 8  C instrument free visual output Released to market
Lts,China amplification instrument free DNA extraction
Xpert Cepheid Inc., USA rpoB PCR Automated sample extraction resistance to Rifampicin CE mark and US FDA approval,
WHO endorsement
NEAT Ionia Technologies Nicking enzyme Isothermal 55.8  C e 59.8  C In development
Inc.,USA/Alere, USA amplification reaction
RPA TwistDx, UK/Alere, USA IS6110, IS1081 Recombinase Isothermal 39.8  C Proof of concept study
polymerase published
Truenat Molbio diagnostics Pvt. Ribonucleoside PCR Miniaturized chip based Semi automated DNA Released to market CEmark
Ltd., India diphosphate extraction
VerePLEX Lab Veredus Laboratories, 16S RNA PCR Microarray technology Rifampicin and issoniazid Released for research use
On Chip Singapore resistance plus nne non-TB mycobacteria
Genedrive Epistem Ltd, UK REP13E1 2 rpoB PCR Paper based DNAextraction technology Rifampicin Field trails
resistance

Cl Cl
H H H
H OH
OH OH OH
NC NC NC
NC

OH OH
N N
N N H
H H
H
48 49 50 51

Cl Cl
H
H H
H OH
OH OH
NC NC
NC NC
H O
O
N OH
N H N
NH H H
52 53 54 55

Cl Cl
H H H
H OH OH
NC
NC NC NC
H
H
H
NH N
NH N H
H
56 57 58 59
Cl
Cl
H H
H
OH OH
NC NC OH
NC
OH OH
OH
N N O
H H N
H
60 61 62

Cl Cl
H H

HO CN

O CN
N N
H H
63 64

Fig. 7. Structure of Indole alkaloids having promising antitubercular activity.

 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544 517

Fig. 8. Structure of Indole alkaloids (Contd.).

7.1.2.3. Micro broth dilution. Sample in 96 well microplates has
benefits of low cost, small sample requirement and potential for
automation. Middelbrook 7H9 broth was used with glycerol, cata-
lase, oleic acid, dextrose, albumin for the culture of Mycobacteria
and quantify by turbidity in liquid medium. Redox indicators such
as Alamar blue determine the sensitivity and speed of assay. It can
be visualized by colorimetric method i.e. at absorbance 570 nm or
fluorimetrically at 530 nm [203,208]. Hence, this allows to perform
high-throughput antimycobacterial screening assays in microplates
using spectrophotometer or fluorimeter.
7.1.2.4. Agar diffusion. It is well diffusion assay used in antimicro-
bial evaluation of natural products and indicates merely inhibition
of growth at any concentration with respect to concentration
gradient. Area under zone of inhibition depends on rate of growth
of microbes and rate of diffusion and size of zone indicates mi-
crobial susceptibility and resistance to specific antibiotics. Agar
diffusion assay was not comfortable with mycobacteria as its cell
wall is lipophilic and less permeable to non-polar compounds
[209]. Less polar compounds diffuse more slowly compared to polar
compounds resulting in small zone of inhibition indicating less
potent antimicrobial activity.
reduce nitrate into nitrite can be measured by Griess method.
Colorimetric estimation of resistance or susceptibility of
M. tuberculosis to natural phytoconstituents or drug has been
characterized in nitrate reductase method. This technique was
introduced to detect differentiation of M. tuberculosis from other
Mycobacteria sp. and evaluation of medicinal plant activity as
antimycobacterials [213,214]. In this method, potassium nitrate is
inoculated with culture media, which leads to reduction of nitrate
into nitrite by using colorimetric technique. Compared to BACTEC
460 TB system, nitrate reductase assay (NRA) has 100% and 100%
results for rifampicin, 75% and 98% for ethambutol, 95% and 83% for
streptomycin, 97% and 96% for isoniazid, respectively. A fresh study
suggests that NRA was directly used for sputum culture. Solis and
his co-workers reported the sensitivity and specificity of NRA to
Lowenstein Jensen medium for resistant M. Tb for isoniazid and

7.1.2.5. Reporter gene assay. Reporter genes are used as alternative

to redox dyes in which plasmids are introduced to help in deter-
mination of bacterial viability by measuring level of luminescent or
fluorescent proteins. Proteins such as green fluorescent protein
[210,211] or red fluorescent protein also help in easy determination
of growth and inhibition kinetics [212].

7.1.2.6. Nitrate reductase assay. The capacity of M. tuberculosis to Fig. 9. Structure of globospiramine.
518 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544
C6H5
F O
C6H5
F O
N HN N
H 7.2.2. Tuberculin test
N S
H HN
75 76
Fig. 10. Structure of synthetic indole alkaloids active against tuberculosis.
rifampicin [215]. While Musa with his colleagues indicated the
evaluation of NRA for drug susceptibility test for M. tuberculosis
directly on smear positive sputum having acid-fast bacilli per mi-
croscopy field [216]. These studies reflect the importance of NRA for
detection of resistant M. tuberculosis in sputum [217].
7.1.2.7. Low oxygen bioassay. In present scenario, the available
antimycobacterial drugs cannot efficiently eradicate M. tuberculosis
as it has a power of dormancy that lead to failed or prolonged
regimen for tuberculosis [218e220]. Dormant Mycobacterium ap-
pears to be an obstacle towards new drug discovery against latent
tuberculosis [221]. In this assay, hypoxia or low oxygen environ-
ment is used to test non-replicating Mycobacteria [222,223]. Way-
ne's hypoxic model is designed for in vitro evaluation of novel
compounds in spite of its low throughput capability [221,224]. Cho
et al. has resolved luminescence based, high throughput, hypoxic
recovery assay for novel compounds against non-replicating
mycobacteria using M. Tb H37Rv strain containing plasmid acet-
amidase promoter propulsive a bacterial luciferase gene [121].
7.1.3. Toxicity and selectivity
Above-mentioned techniques help a lot in lead development
from natural products and following to this cytotoxicity to cells
should be investigated in order to confirm sample toxicity and
selectivity for Mycobacteria. In discovery of new leads for antitu-
bercular drug, selectivity and cell toxicity studies is key factor that
led to determination of mycobacterial MIC, IC50 value and selec-
tivity index [225,226].
7.2. Diagnostic tools for tuberculosis
Various techniques were used for the detection of tuberculosis
infection. Major of these includes tuberculin test performed on skin
and called as skin test. To diagnose the infection of M. tuberculosis,
Interferon-Gamma Release Assays (IGRAs) are convenient tools
refers to whole blood test. These tests principally trials the immune
reactivity of individuals infected with tuberculosis, white blood
cells released interferon-gamma (IFN-g) when mixed with anti-
gens. Sputum investigation is also a confirmatory tool for
M. tuberculosis. Radiography investigation of chest is also a tech-
nique to detect impact of tuberculosis. The nucleic acid amplifica-
tion tests are also one of the useful diagnostic tools for TB detection.
Below are enlisted techniques as a confirmatory tool for TB.
7.2.1. Sputum investigation
Sputum is thick mucus expelled from bronchi or lungs through
coughing for culture and detects the presence of any pathogenic
microbes. In this, sputum of infected person was cultured in
appropriate nutrient media. Cultured sample is incubated for 2e3
weeks and then observe for bacterial growth. If no bacterial growth
were seen, it implies negative to bacterial invasion. If colony of
bacteria was observed, it confirms the presence of M. tuberculosis.
C3H7 The detection of tuberculosis was attained using this technique in
less than 20 min at 39  C in treated sputum with high specificity
[227].
N Tuberculin is injected under the skin of patient. In case of
Mycobacterium infection, area around injection site becomes red
O affirming tuberculosis. In case of BCG vaccinated person, tuberculin
test shows positive result so confirmatory test is further required.
7.2.3. Radiographic investigation
Infected lungs from M. tuberculosis present the infiltrates and
cavities in upper lungs or any other region. Hilar lymphadenopathy
is also characterized in case of pulmonary TB.
7.2.4. Nucleic acid techniques
The nucleic acid amplification tests (NAATs) were introduced in
the year 1990s and termed as a new generation diagnostic tools for
detection of new TB cases in hours. In previous, nucleic acid
amplification test techniques were found less sensitive in compare
to culture but more sensitive than microscopy and the ability to
safely detection of TB cases without relocation to a specialist lab-
oratory [228]. Recently, some nucleic acid amplification test prod-
ucts for tuberculosis have been shared in the market to acquire
their reduced cost, results in short time duration and enhanced
strength with expediency [229]. The development of NAAT tech-
niques have been depicted inb Table 2.
8. Plants: a harry potter stick for tuberculosis
Since long back, natural product have shown enormous poten-
tial to cure different disease and widely explore to achieve a po-
tential lead for the drug development [230]. The urge for discovery
and development of new novel antitubercular drugs leading from
natural resources to decrease the burden of deadly disease also
known as “Captain of Death”, is highlighted by the number of re-
searchers [230e234]. Novel scaffolds for TB from natural origin has
been well mentioned and focused on some potential molecules
with promising efficacy [235]. WHO targeted 2035 for complete
eradication (95%) of disease or death due to tuberculosis by the
means of excellent regimen keeping in mind the safety, efficacy and
duration of treatment [231]. Lot of reviews proved the efficacy and
importance of natural products as lead molecule for many diseases
[234e238]. Mdluli et al., mentioned notable compounds from
natural source which were proven as useful lead for antitubercular
agents [239]. Drug discovery for TB is not only confined to plants
but it also encompasses the fungi, marine, mineral, bacterial and
animal source of drug. The plethoras of compounds were embarked
in literature with awesome inhibitory concentration to active as
well as dormant M. Tb [240e242]. Apart from number of ongoing
projects in the field of natural product inspired antimycobacterial
drug discovery and development, there were some notable reasons
listed below, which lead to failure of novel therapeutic compounds
as antimycobacterial agents:
a) Structural complexity of natural product compounds,
b) Low yield of active moiety from natural source,
Fig. 11. Structure of thiadiazolylhydrazones derivatives.
 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544 519

range of pharmacological activities [245]. Indomethacin, strychnine

and many others alkaloids are the well-known representative ex-
amples to justify the effectiveness of indole alkaloids for their
antimycobacterial efficacy.
Blue Green algae contain several secondary metabolites having
potential antimycobacterial activity. All the isolated alkaloids were
screened for their activities against tuberculosis, where many of
them showed significant biological efficacy and may be considered
lead molecule for the treatment of tuberculosis [246]. Four new
indole alkaloids, including Ambiguine K (48), Ambiguine L (49),
Ambiguine M (50), and Ambiguine N (51) were isolated from
Fischerella ambigua, where they showed significant inhibitory ac-
tivity against M. tuberculosis (H37Rv) with MIC of 6.6, 11.5, 7.5, and
46.7 mM, respectively. Six different isonitrile analogues of indole
alkaloids were showed moderate action on M. tuberculosis. These
Fig. 12. Structure of cyclohepta[b]indoles analogues. are ambiguine A isonitrile (52), ambiguine C isonitrile (53), ambi-
guine E isonitrile (54), ambiguine I isonitrile (55), hapalindole G
c) Absence of precis raw data from academic research
(56), and hapalindole H (57) with MIC value of 46.7,7.0, 21.0, 13.1,
d) Sometimes false data provided by researchers on the name of
6.8, and 58.8 mM, respectively [247]. Later on, new ambiguine iso-
drug development,
nitriles K, L, M, N, and O (58-62) were found efficacious against
e) Evaluating the safety profile of drug without interfering with
Mycobacterium. Ambiguine K isonitrile (58) possess the potent ac-
other pathway,
tivity with MIC value of 2.8 mg/mL against M. tuberculosis H37Rv
f) Drug-drug interactions,
strain. Ambiguine L (59), ambiguine M (60) and ambiguine N (61)
g) Optimization of dose for its antimycobacterial activity.
have moderate effect against M. tuberculosis with MIC of 4.5, 3.3
and 10.9 mg/mL respectively [247]. In further investigation,
Furthermore, the available literature has no sign on the safety
F. ambigua has been successfully isolated and reported in addition
profile of isolated compounds as shown by means of the selectivity
to new indole alkaloids, fischambiguine B (63), ambiguine G iso-
index (SI); therefore there is an increased demand to examine the
nitrile (64) which showed significant inhibition to H37Rv
toxicological profile of purified and semi-purified compounds. This
M. tuberculosis at MIC of 2.0 and 53.7 mM, respectively. The former
could be a rough assignment to meet the mentioned problems
one has an IC50 value of 128 mM, which makes it potent anti-
without improved funding for antitubercular drug discovery and
mycobacterial agent (Fig. 7) [247].
development pipeline via good-coordinated global efforts.
Likewise, six indole type alkaloids viz. (þ)-manilamine, N-
Even though combinatorial chemistry continues to be key factor
methyl angusilobine, 19,20- (E) vallesamine, angustilobine B N-
in the drug development process for antimycobacterials, it is
oxide, 20(S)-tubotaiwine, 6,7-seco-angustilobine (65-70) were
remarkable that the inclination toward the synthesis of multifac-
isolated from the methanol leaves extract of Alstonia scholar isthat
eted natural-product database has continued. To researchers, a
displayed 50e89% inhibition of M. tuberculosis H37Rv using an MIC
multidisciplinary trials to drug discovery, concerning the genera-
of 50 mg/mL [248].
tion of efficacious novel molecular variety from natural sources,
The root of Tabernaemontana elegans possesses indole alkaloids
shared with total and combinatorial synthetic procedure and
voacangine (71) and dregamine (72) with MIC value of 128e256 mg/
including the management of biosynthetic pathways, will persist to
mL against Mycobacterium sp [249]. Another source for indole
afford the best explanation to the current output crisis facing the
analogue was Chaetomium globosum, which was reported with
scientific society engaged in drug discovery and development.
echinuline (73) moderately active against M. tuberculosis with MIC
Antitubercular drug discovery and development from natural
value of 169.9 mg/mL (Fig. 8) [250].
sources need to overcome various hurdles such as finding effica-
Voacanga globosa was discovered with spiroindole alkaloid
cious lead within limits of safety profile and identify the hits with
named globospiramine (74) (Fig. 9). This compound has potent
preclinical stages of drug discovery. Another major challenge is to
activity against M. tuberculosis H37Rv with MIC value of 4e5.2 mg/
characterized novel entities for de novo structure elucidation. To
mL [251]. The antimycobacterial activity of globospiramine is de-
fasten the drug discovery and development program for TB, we
pends on the presence or absence of unoxidized C-20 and hydroxyl
need an upgraded technology with high-throughput screening
group at C-3 on spriobisindole moiety [251].
(HTS) of natural product leads [243,244]. In this review, the pre-
In sight of new synthetic indole derivative Cihan et al. synthe-
viously mentioned bottlenecks are assessed with different points
sized hydrazone (75) and spirothiazolidinone analogue (76) of 5-
and focus on scientific tasks to overcome in drug discovery and
fluoro-3-phenyl-1H-indole scaffold and evaluated for its anti-
development program for antitubercular drugs. Hereafter, we
mycobacterial efficacy (Fig. 10). They found the efficacy of these
emphasize on the recent trends in the field of mycobacteriology
synthesized derivatives against the M. tuberculosis H37Rv with the
specifically by providing different methods available for diagnosis,
assay, available treatments, possible targets and effective anti-
mycobacterial alkaloids and their synthetic analogues to justify role
of phytoconstituents in the treatment of tuberculosis.

9. Alkaloids with significant antimycobacterial activity

9.1. Indole alkaloids

Indole-based heterocyclic compounds are identified as the 3rd

most common skeleton found in drugs known to exhibit wide Fig. 13. Structure of pentacyclic indole alkaloid.
520 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544

Fig. 17. Structure of celastramycin A.

Fig. 14. Structure of Pyrrole alkaloids.

Fig. 18. Structure of banegasine.

Fig. 15. Structure of vermelhotin.

against M. tuberculosis with MIC value of 6.1 and 64 mg/mL,

MIC value of 6.25 mg/mL. The methyl or propyl group on 8th posi- respectively [257,258].
tion of spiro ring is responsible for its potency as antimycobacterial The compound, Vermelhotin (86) obtained during the investi-
agent [252]. gation of Hintonia latiflora fungus, displayed significant anti-
Further studies revealed that thiadiazolylhydrazones derivatives mycobacterial activity against M. tuberculosis H37Rv with an MIC
(cyclic analogues) i.e. indole-3-carboxaldehyde 1,3,4-thiadiazol-2- value of 3.1 mg/mL (Fig. 15) [134,259].
yl-hydrazone has potent activity against M. bovis BCG with inhibi- Solsodomine A (87), potent antimycobacterial natural com-
tory concentration of 7.81 mg/mL (77) (Fig. 11). Absitence of anti- pound was isolated from Solanum sodomaeum. This alkaloid ceased
mycobacterial activity of indole ring was resulted due to the growth of M. intracellulare with minimum inhibition concen-
substitution of bromine at C-5 position of ring. The main possible tration of 10.0 mg/mL [260]. Nitropyrrole analogue, pyrrolnitrin (88)
reason for loss of antimycobacterial activity was lipophilicity and did not lead to any significant improvement in the MIC values of
size of bromine which may cause steric hindrance [253]. 4e16 mg/mL against M. tuberculosis, M. avium and M. smegmatis
Heterocyclic compounds such as pyrazolo- (78), isoxazolo- (79), (Fig. 16) [261].
pyrimido- (80) and mercaptopyrimido- (81) substitution at cyclo- Based on potent anitubercular activities with imidazole skeleton
hepta[b]indoles resulted in compounds with potent activity against [260], a series of synthetic analogues of imidazole with spacer as
M. tuberculosis (Fig. 12). These derivatives were synthesized by
cyclocondesation of 7-hydroxymethylene-7, 8, 9, 10-
tetrahydrocyclohepta[b]indol-6(5H)-ones using nucleophiles.
Resazurin microtitre assay was used to evaluate the in vitro anti-
mycobacterial activity of these substituated analogues and the
chloro substituated compound showed maximum potency against
M. tuberculosis H37Rv with MIC 3.12 mg/mL [254].
Pentacyclic indole alkaloids were evaluated for their antituber-
cular activites although biological activities were not increased
than molecules having simple heterocyclic core. Ibogaine (82) and
voacangine (83) isolated from Tabernaemontana citrifolia found to
inhibit the Mycobacterium sp. with MIC values of 50e100 mg/mL
(Fig. 13) [255,256].

9.2. Pyrrole alkaloids

Carribean sponge Prosuberites laughlini possesses two bromine-

containing pyrrole as hymenidin (84) and monobromo isophakellin
(85) (Fig. 14). These compounds have shown moderate potency

Fig. 16. Structure of solsodomine A and pyrrolnitrin. Fig. 19. Structure of Diarylpyrrole alkaloids.
 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544
Fig. 20. Structure of BM-212.
Fig. 21. Structure of diarylpyrrole derivatives.
well without spacer has been developed [262]. Futhermore, a series
of glycosylated aminoester having imidazole were achieved and
screened for antitubercular efficacy [263]. Some imidazle-based
compounds have shown interesting antitubercular activity [262].
A dichloropyrrole alkaloid was isolated through fermentation of
Streptomyces strain with broad-spectrum antimycobacterial activ-
ity. Celastramycin A (89) (Fig. 17) exhibited the MIC value of
0.05e3.1 mg/mL against M. vaccae, M. fortuitum, M. smegmatis
Fig. 22. Structure of cyclo-penta[b]fluorene ring type alkaloids.
521
Fig. 23. Structure of Dimeric alkaloid.
strains [264].
Indian shrub named Adhatoda vasica possesses vasicine and its
semi synthetic analogues bromhexine and ambroxol were found to
inhibit M. tuberculosis. These alkaloids exhibited antimycbacterial
activity with MIC value of 6e64 mg/mL [265].
Pyrrole analogue banegasine (90), isolated from zoobacterium
Aristabacter necator possess antimycobacterial activity against
M. smegmatis with MIC value of 0.5 mg/mL [23]. Similarly, another
pyrrole analogue pyrrolnitrin (MIC 4e16 mg/mL) with banegasine
showed potent activity against M. tuberculosis, M. smegmatis, and
M. avium with inhibitory concentration of 0.075 mg/mL (Fig. 18)
[261].
Three metabolites namly denigrins A-C (91-93) were isolated
from the marine sponge Dendrilla nigra, displayed potent anti-
mycobacterial activity against M. tuberculosis H37Rv with the MIC
values of 16, 32 and 4 mg/mL, respectively (Fig. 19) [266].
Based on the structure and activity of denigrin A, a series of
maleimide substituted derivatives were obtained by reacting ani-
lines with maleic anhydride in presence of acetic anhydride and
sodium acetate and developed molecules were evaluated for
in vitro antitubercular activity against M. tuberculosis H37Rv using
MABA method. Three of them e.g. PA4, PA8 and PA14 showed
potent activity against M. tuberculosis H37Rv with MIC value of 6.25,
3.125, 3.125 mg/mL respectively [267].
Synthetic diarylpyrroles are well documented for anti-
mycobacterial activity and among them BM- 212 (94) (Fig. 20)
analogues shown promising efficacy against Mycobacterium with
MIC value of 1.0 mg/mL. This is obvious to conclude that the pres-
ence of (thiomorpholine-4-yl) methyl at C-3 postition of 1, 5-
diarylpyrrole is responsible for the antitubercular activity [267].
Several diarylpyrrole derivatives such as novel analogues 95a,
95b, and 95c have most potent antitubercular activity with MIC
value of 1, 0.4 and 0.5 mg/mL, respectively which was comparable to
standard antimycobacterial isoniazid and Rifampicin. They are
potent against intracellular M. tuberculosis with MIC value three
times lesser than the standard one. Compounds 95a, 95b, 95c are
very effective against other strains of Mycobacterium and resistant
M. Tb [268,269]. Furthermore, synthesis of other analogues resulted
in 95d-t compounds in which they shown activity against Myco-
bacterium as well as resistant strains. Compound 95 exert most
effective inhibition against Mycobacterium 103471 with MIC value
of 0.125 mg/mL similar to MIC of isoniazid. Other compounds 95d,
95 g, 95 l, 95 m, 95r, 95s have similar MIC to rifampicin i.e. 0.25 mg/
mL, whereas 95 k, 95p and streptomycin has similar MIC of 0.5 mg/
mL [267].
Compound 95t exhibits its antitubercular activity against
M. tuberculosis CIP 103471, M. tuberculosis H37Rv ATCC 27294 and
the rifampicin-resistant M. tuberculosis ATCC 35838 with MIC value
of 0.25 mg/mL (Fig. 21) [270].
Three cyclopenta[b]fluorene type alkaloids, phomapyrrolidones
A-C (96, 97, and 98) were obtained from the endophytic fungal
strain Phoma sp. These compound were found to exhibit good to
522 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544
Fig. 24. Structure of Carbazole alkaloids having antitubercular activities.
Fig. 25. Structure of carbazole analogues isolated from bark of M. hirsutum.
significant antitubercular activity in blue assay with the MIC values
of 20.1, 5.9 and 5.2 mg/mL, respectively (Fig. 22) [271].
Pyrrole-based dimeric alkaloid have shown promising efficacy
against tuberculosis. For example, Trichoderma, a seed fungus (BCC
7579) possess hirsutellone F (99) alkaloid which exhibited anti-
mycobacterial activity with MIC of 3.12 mg/mL (Fig. 23) [272].
9.3. Carbazole alkaloids
About ninety years later the discovery of carbazole heterocycle,
Fig. 26. Structure of Indoloquinoline alkaloids.
the antimicrobial properties of 3-formyl-1-methoxycarbazole (100)
(commonly known as murrayanine, which was isolated from the
Murraya koenigii) commenced a strong interest of medicinal
chemist and since then this skeleton have shown enormous po-
tential in drug discovery and development due to their fascinating
structural features and wide range of biological activities [273].
7-Hydoxymukonal (101) was isolated from Clausena harmandi-
ana, which inhibits the growth of M. tuberculosis (H37Ra) with MIC
of 25 mg/mL [274]. Fluroclausine-A (102) and 7-hydroxy-hepta-
phylline (103) have been extracted from the air-dried roots of
C. guillaumine and displayed week antimycobacterial activity with
MIC value of 25 mg/mL (Fig. 24) [275]. Another carbazole alkaloids,
such as rhizomes (104), 3-methoxycarbonyl carbazole (105),
clauszoline J (106) and 2-hydroxy-3-formyl-7-methoxy-carbazole
(101) were isolated from the roots and were shown moderate ef-
ficacy on M. tuberculosis with MIC value of 100, 50, 100, and 100 mg/
mL, respectively [276].
The carbazoles derivatives such as 107, 108, 109 and 110 were
isolated from bark of M. hirsutum has shown potent anti-
mycobacterial activity with MIC of 31.5, 14.3, 42.3, and 15.6 mg/mL,
respectively (Fig. 25) [277].
9.4. Indoloquinoline alkaloids
Cryptolepis sanguinolenta contains indoloquinoline alkaloids viz.
cryptolepine (111), neocryptolepine (112), dimer biscryptolepine
(113) which was have been found effective against M. fortuitum, a
species alternative to M. tuberculosis with MIC value of 16 mg/mL,
31 mg/mL, 6.25 mg/mL, respectively (Fig. 26) [278,279].
Two canthin-6-one alkaloids (114 and 115) were isolated from
Allium neapolitanum an ornamental flowering plant possess anti-
mycobacterial activity against M. smegmatis and M. phlei (Fig. 27).
They have shown moderate action with reported MIC value of
8e32 mg/mL. Interestingly, synthetic analogue of alkaloid 115 re-
ported with increase in antimycobacterial activity eight folds with
Fig. 27. Structure of canthin-6-one alkaloid.
 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544 523

Fig. 28. Structure of manzamine alkaloids.

MIC value of 2.0 mg/mL [280].
9.5. Manzamine alkaloids
Four manzamine alkaloids (-)-8-hydroxymanzamine A (116),
(-)-manzamine F (117), manzamine A (118), and (þ)-8- hydrox-
ymanzamine A (119) were tested against M. tuberculosis H37Rv.
They exhibited MICs of 0.91, 12.5, 1.56, and 6.25 mg/mL, respectively
[244,281]. Manazamine derivatives manazamine Y (120), man-
domanazamine A (121) and mandomanazamine B (122) were iso-
lated from Acanthostrongylophora sp. and showed potent activity
against M. tuberculosis H37Rv with MICs of 1.9, 1.5 and 5.2 mg/mL
respectively. The metabolite 6-hydroxymanzamine E (123) and 8-
hydroxymanzamine J (124), isolated from same species, exhibited
an MIC of 0.4 mg/mL against M. tuberculosis H37Rv and an IC50 of
3.5 mg/mL against M. intracellulare (Fig. 28) [244,282,283].
4-Methoxy-2-phenylquinoline (125), graveolinine (126), and
kokusagine (127) were isolated from Lunasia amara exhibited
antitubercular activity against H37Rv strain and reported MIC of
16 mg/mL [286]. The quinoline alkaloids from Zanthoxylum
wutaiense were reported g-fagarine (128) and dictamine (129).
Both alkaloids showed MIC value of 30 mg/mL (Fig. 29) [287].
Based on antitubercular activity associated with quinoline
scaffold, two novel series have been recently developed through
conjugation of quinoline skeleton with chalcone as well pyrazoline
motifs and tested for their antibacterial and anti-tubercular activ-
ities [288]. Some of them exhibited good to appreciable antibac-
terial activity against the tested bacterial strains. Two of them
found to be the promising candidates exhibiting MIC 4 mg/mL

9.6. Quinoline alkaloids

Several quinoline-based heterocyclic compounds have been

explored to search out a lead against antituberculosis drug. This
heterocyclic core placed important position in medicinal chemistry
and several natural products possessing quinoline skeleton are well
explored for their antitubercular potential. Representative exam-
ples include, Bedaquiline, the first FDA-approved new chemical
entity to fight multidrug-resistant tuberculosis in the last forty
years. Several modification on this drug were attempted to achieve
the most promising one useful to fight against tuberculosis [284]. In
order to increase the antitubercular efficacy, the quinoline ring was
replaced with a naphthalene ring resulting to a new type of triar-
ylbutanol skeleton [285]. Fig. 29. Structure of Quinoline alkaloids.
524 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544
Fig. 30. Structure of quinolines as antitubercular agent.
Fig. 31. Structure of Quinolones alkaloids isolated from Evodia rutaecarpea.
against B. subtilis MTCC 121 and M. luteus MTCC 2470 and few
conjugates displayed moderate anti-tubercular activity against
both H37RV as well as RifR strains. The binding modes and effect of
the C4 quinoline substitution on the activity was studied using
computational techniques.
Several quinoline derivatives, for example 3-benzyl-6-bromo-2-
methoxy quinolines were developed through molecular modelling
techniques found to be active against M. tuberculosis H37Rv strain
[289]. Some 7-chloro quinoline derivatives were effective against
multi-drug resistant tuberculosis [290]. Considering mefloquine as
the lead, a series of quinoline with some active pharmacophores
such as hydrazones, ureas, thioureas and pyrazoles attached at the
4th position have been developed as anti-tubercular agents [291].
Fig. 32. Structure of isoquinoline alkaloids active against tuberculosis.
Fig. 33. Structure of Bis-benzylisoquinoline alkaloids isolated from Tiliacora triandra.
Interestingly, quinoline-based molecules having an isoxazole as a
side chain was proven to be active against M. tuberculosis [292].
Investigation on Angostura bark (Galipea officinalis) established
a series of six new alkaloids 130, 131, 132, 133, 134, and 135 which
exhibited antimycobacterial activity against M. tuberculosis with
MIC value of 6.25e50 mg/mL. The antitubercular activity was found
due to the presence of quinoline ring and 4-methoxyl group. These
alkaloids were present in ethanolic extract of G. officinalis (Fig. 30)
[293] (see Fig. 31).
A series of quinolone alkaloids i.e. 136, 137, 138, 139, and 140,
isolated from Evodia rutaecarpea have shown good potency against
M. tuberculosis. They inhibited the Mycobacteria at the MIC of
2e362 mg/mL (Fig. 32) [294].
9.7. Isoquinoline alkaloid
Various alkaloids in solvent extracts of natural origin have
shown moderate to strong potency against mycobacterial species.
For this, alkaloids from leaves or other parts of plant were taken,
purification and characterization of compound were followed by
mycobacterial studies of these extract. In some cases like in the leaf
of Justicia adhatoda, purification was done by crystallization. For
that crude alkaloid were dissolved in the boiling methanol followed
Fig. 34. Structure of tetrandrine alkaloid.
 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544
Fig. 35. Structure of ecteinascidin alkaloids.
by filtration and concentration until the alkaloids started crystal-
lising out. Six different quinazoline alkaloids, for example, vasico-
line, vasicolinone, vasicinone, vasicine, adhatodine and anisotine
were successfully identified as lead molecules against tuberculosis
[265]. Crude DCM-methanolic extract of the, Voacanga megacarpa,
showed moderate inhibitory activity (MIC ¼ 64 mg/mL) against
M. tuberculosis H37Rv [295e297]. Four isoquinoline alkaloids such
as dioxoaporphine (141), ouregidione (142), oxoaporphine lir-
iodenine (143), and oxostephanine (144) were isolated from CHCl3
extract of Pseuduvaria setosa. Out of four alkaloids, oxoaporphine-
liriodenine (143) was found to be the most active molecule against
M. tuberculosis with an MIC of 12.5 mg/mL (Fig. 32) [298].
Bisbenzylisoquinoline alkaloid have been isolated from natural
resources and evaluated for their antitubercular efficacy. For
example, isoquinoline derivatives tiliacorinine (145), 2’- ortilia-
corinine (146), and tiliacorine (147) (Fig. 33) were isolated from
Tiliacora triandra and exhibited antimycobacterial activity against
M. Tb with MIC value of 6.2, 3.1, and 3.1 mg/mL respectively [299].
Tetrandrine (148) (Fig. 34), isolated from Stephania tetrandra
exhibited antimycobacterial activity in combination with isoniazid
or ethambutol at the MIC value of 0.25e1.25 mg/mL by inhibiting
drug efflux [300,301].
Ecteinascidin 743 (149) isolated from Caribbean ascidian Ectei-
nascidia turbinata was reported to exhibit antimycobacterial activ-
ity against M. avium with zone of inhibition at 10 mg/disc loading
[302e304]. Another alkaloid ecteinascidin 770 (150) and ectei-
nascidin 786 (151) isolated from different species namely Ectei-
nascidia thurstoni native of Thailand owes antitubercular activity
against M. tuberculosis H37Ra strain with MIC value of 0.1 and 1.6 mg/
mL, respectively (Fig. 35) [305].
Three aporphine alkaloids (152-154) (Fig. 36) were isolated from
Colombian plants Ocotea macrophylla, exhibited the moderate
525
antimycobacterial activity against the M. tuberculosis with the MIC
values of 64, 128 and 4 mg/mL, respectively [306]. Similarly, an
aporphine alkaloid, dicentrinone (155) was isolated from the Ste-
phania dinklagei exhibited the moderate antimycobacterial activity
with an MIC value of 50 mg/mL against M. tuberculosis H37Rv
[307,308].
A novel antitubercular agent effective against M. TB (H37Ra) with
MIC of 6.25 mg/mL, bidebiline E (dimericaporphine) (156), was
isolated from the roots of P. cerasoides. Oxoaporphine alkaloids
named liriodenine (157) and oxostephanine (158) obtained from
Pseuduvaria setosa, exhibited antimycobacterial activity with MICs
of 12.5 and 25 mg/mL, respectively [298]. A study of flowers of
Goniothalamus laoticus revealed a known aporphine alkaloid
(-)-nordicentrine (159), which showed activity against
M. tuberculosis H37Ra with a MIC of 12.5 mg/mL (Fig. 36) [309].
Two benzophenanthridine alkaloid namely, decarine (160) and
6-acetonyldihydronitidine (161) were isolated from the plant Zan-
thoxylum capense exhibited significant antimycobacterial activity
against M. tuberculosis H37Rv with the MIC values of 3.1 and 6.2 mg/
mL, respectively (Fig. 37) [310].
Extensive structure activity study revealed that the benzophe-
nanthridine alkaloids nitidine, chelirubine and macarpine were
potent inhibitor against M. tuberculosis H37Rv with MIC value of
12.5 mg/mL [311]. This is interesting to note that methoxy or
methylene dioxy substitution in benzophenanthridine alkaloids
plays a decisive role in the antimycobacterial activity.
Furthermore, considering the antitubercular potency of alka-
loids containing isoquinaline heterocyclic ring, a benzylisoquino-
line alkaloids have also been evaluated to search a lead molecule
suitable for drug development againd tuberculosis. Medicinal plant
families such as Berberifaceae, Menispermaceae possess the active
constituents, which are reported for their good antimycobacterial
activities. Berberine (162), a potent antimicrobial alkaloid possesses
antimycobacterial activity against M. smegmatis, and
M. intracellulare with MIC value of 0.78e1.56 mg/mL. Berberine also
inhibits M. tuberculosis with MIC value of 25 mg/mL (Fig. 38)
[312e315].
Blood root also known as Sanguinaria canadensis, was reported
with sanguinarine (163) and chelerythrine (164) (iminium salt),
which has a better lipophilicity and active against M. Tb with MIC
value of 24.5 and 14.3 mg/mL, respectively (Fig. 39) [316].
Few alkaloids which possess the good antimycobacterial activity
were isolated from Duguetia species. For example, anonaine (165),
xylopine (166), anolobine (167), and jatrorrhizine (168) exhibits
potential inhibition against Mycobacterium species and observed
MIC value with 12e50 mg/mL, 12e50 mg/mL, 6e25 mg/mL, <100 mg/
mL, respectively (Fig. 40) [317,318].
9.8. Pyrrolo [2,1-b]quinazoline alkaloids
Extracts from Boophone disticha herb gave three alkaloids (gal-
anthamine, lycorine, and crinine) to treat TB [319]. Petroleum ether
extracts of leaf of Arctotis auriculata resulted alkaloids with other
phytochemicals and displayed MIC of 8.5 mg/mL against
M. smegmatis. Antimycobacterial activity of leaf of Samanea saman
was observed using radiospirometric BACTEC 460 TB assay method
(two-fold dilution) [320]. The alcoholic extract of Samanea saman
showed activity against M. tuberculosis at 50 mg/mL.
Justicia adhatoda, also called as vasaka was investigated to have
the potential antitubercular agents where a series of interesting
quinazoline alkaloids were isolated which showed significant
antimycobacterial activity. Six different quinazoline alkaloids,
namely vasicoline (169), vasicolinone (170), vasicinone (171),
vasicine (172), adhatodine (173) and anisotine (174) (Fig. 41) were
extracted from the leaf of Justicia adhatoda, have shown to
526 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544
Fig. 36. Structure of Aporphine alkaloids.
Fig. 37. Structure of Benzophenanthridine alkaloids.
posses activity against M. tuberculosis [321]. Furthermore, in-silico
investigation affirmed that these alkaloids hinder b-ketoacylacyl-
transporter protein synthase III (FabH), an enzyme required in the
Fig. 38. Structure of berberine.
first step of fatty acid biosynthesis, prompting poor cell wall
development and vitality of bacilli [322].
Adhatoda vasica, which is traditionally used to cure colds, cough,
and other respiratory disorders, possess antimycobacterial com-
pounds like vasicine acetate (175) alongwith 2-acetyl benzylamine
that inhibited both, sensitive and MDR strains of M. tuberculosis at
MIC of 50 and 200 mg/mL, respectively [323].
Azaindoloquinazolinedione alkaloid, namely tryptanthrin (176)
was isolated from Chinese Strobilanthes cusia and on nbiological
screening showed active against sensitive and multiple resistant
M. tuberculosis strains with MIC of 16e64 pg/mL in vitro (Fig. 41)
[324].
9.9. Cyclostelletamine alkaloids
Cyclostelletamines alkaloids were isolated from sea sponge
Pachychalina sp. namely cyclostelletamine A (177),
Fig. 39. Structure of sanguinarine and chelerythrine.
 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544
Fig. 40. Structure of miscellaneous alkaloids.
cyclostelletamine B (178), cyclostelletamine C (179), cyclostellet-
amine D (180), cyclostelletamine E (181), and cyclostelletamine F
(182). These alkaloids showed significant activity against
M. tuberculosis (H37Rv) with value of MIC 32.0, 4.0, 4.0, 8.0, 11.0 and
Fig. 41. Structure of pyrrolo [2,1-b]quinazoline-based antimycobacterial alkaloids isolated from plant extracts.
527
8.0 mg/mL, respectively. SAR of these alkaloids indicates that the
length of alkyl chain for the antitubercular activity i.e. smaller alkyl
chain has excellent activity compared to larger one. Furthermore,
synthetic analogues of cyclostelletamines i.e. cyclostelletamine G
(183), cyclostelletamine H (184), cyclostelletamine I (185), cyclo-
stelletamine J (186), and cyclostelletamine K (187) also possessed
bactericidal effect against M. tuberculosis. The minimum inhibitory
concentration for the compounds were 4.6, 9.3, 6.6, 5.3, 4.6 mg/mL,
respectively (Fig. 42) [325].
9.10. Pyridoacridone alkaloids
Sea squirts Lissoclinum notti and Diplosoma extracts showed the
presence of ascididemin (188), diplamine (189), isodiplamine (190),
lissoclinidine (191), kuanoniamine D (192) and shermilamine B
(193), where these alkaloids known to inhibit M. tuberculosis
growth with MIC value of 0.35, 17, 17, 17, 34 and 32 mM, respectively.
The IC50 level of ascididemin is around 0.14 mM, which is highly
toxic to Vero cells that make this molecule not suitable for further
drug development (Fig. 43) [326].
Further investigation revealed two new marine products of
ascididemin class, namely 11-hydroxyascididemin (194) and kua-
noniamine A (195) (Fig. 44), which possess promising antituber-
cular activity against M. tuberculosis H37Rv with MIC value of
>42 mM and 10.7 mM respectively [327,328].
Synthesis of tetracyclic pyrido[2,3,4-kl]acridin-6-one analogues
528 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544

Fig. 44. Structure of Pyridoacridone alkaloids (Contd.).

Fig. 42. Structure of Cyclostelletamine alkaloids.

O
(196, 197, 198, and 199) are also indicative of antimycobacterial O
N
activity as it resembles to the part of strucuture activity relationship N
of 11-hydroxyascididemin. These analogues have reported with
C6H4H3CS
minimum inhibitory concentration against M. tuberculosis H37Rv C6H4H3CS
with values 9.0, 2.20, 0.34, and 1.5 mM respectively (Fig. 45) [329]. N
O
Interestingly, substitution on acridinones ring, such as thio-
phene (200), furan (201), 2,3,4-trisubstitued pyridine ring (202) 196 197
resulted with potent antitubercular activity against Mycobacteria
with MIC value of 0.58, 0.61, and 2.1 mM, respectively. Acridinone O
O
analogue 4-ethylthiopyrido[2,3,4-kl]acridin-6-one (203) was exer- N
N
ted most efficacious inhibition against Mycobacterium H37Rv with
MIC value of 0.34 mM, which was nearby similar to ascididemin H2CH3CS
H3CO
(Fig. 46) [329]. N
Based on the activity profile, a series of simple pyridylmethyl N
198 199

Fig. 45. Structure of synthetic tetracyclic pyrido[2,3,4-kl]acridin-6-one analogues.

amines have been developed and evaluated for their anti-

tubercular activity profile. Few of them exhibited promising abti-
tubercular activity with MIC as low as MIC 1.56 mg/mL [330].

9.11. Aza-anthraquinone alkaloids

Cleistopholine (204) and 3-methoxy sampangine (205) from

Cleistopholis patens and Sampangine (206) from Cananga odorata
exhibited the potent activity against Mycobacterium sp. with MIC
value of 12.5, 1.56 and 0.78 mg/mL, respectively [331,332]. Cleisto-
pholine was also reported in D. vallicola and has same anti-
mycobacterial activity (Fig. 47) [331,333]. In another research

Fig. 43. Structure of Pyridoacridone alkaloids. Fig. 46. Structure of acridinone analogues.
 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544 529

Fig. 47. Structure of aza-anthraquinone alkaloids.

Fig. 50. Structure of Alkamide type alkaloids.

and brachyamide B (211), and the isolated alkaloids 208-211 have

exhibited moderate antitubercular activity against H37Ra strain
with MIC value of 50, 25, 50, and 50 mg/mL respectively (Fig. 48)
[335].
Furthermore, two alkyl amides namely pellitorine (212) and
brachystamide B (213) were isolated from the same source Piper
sarmentosum and possess moderate inhibitory activity against
M. tuberculosis with MIC of 50 and 50 mg/mL, respectively (Fig. 49)

Fig. 48. Structure of pyrrolidine alkaloids isolated from Piper sarmentosum.

program, aza-anthraquinones alkaloid (207) was isolated from

Mitracarpus scaber which on bioevaluation found to inhibit the
growth of M. intracellulare at the concentration of 6.5 mg/mL [334].

9.12. Pyrrolidine alkaloid

Piper sarmentosum, a potent medicinal plant showed the pres-

ence of sarmentine (208), pyrrolidine (209), sarmentosine (210),

Fig. 49. Structure of pellitorine (212) and brachystamide B (213) isolated from Piper
sarmentosum. Fig. 51. Structure of imide alkaloids.
530 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544
Fig. 52. Structure of himanimide alkaloids isolated from Serpula himantoids.
Fig. 53. Structure of epiccocarines A and b.
[335].
Pyrrolidine alkaloid based amides like Alkamide type alkaloids
have also shown promising antitubercular activities. Three
alkaloid amides malyngamide 4 (214), malyngamide A (215) and
malyngamide B (216) were isolated from the red sea marine
cyanobacterium Moorea producens, exhibited antibacterial activity
against M. tuberculosis H37Rv at a concentration of 12.5 mg/mL with
an inhibition of 17, 18 and 10%, respectively [336]. Likewise, an
alkamide, N-isobutyl-(2E,4E)-2,4-tetradecadienamide (217) was
isolated from the roots methanol extract of plant Zanthoxylum
capense. The isolated metabolite displayed good antibacterial
activity against M. tuberculosis H37Rv with an MIC value of 6.2 mg/mL
(Fig. 50) [310].
9.13. Imide alkaloids
Imide alkaloid analogue hirustellones with some structural
modification known for the more potent antimycobacterial activity.
Hirustellone A (218), Hirustellone B (219), Hirustellone C (220), and
Fig. 54. Structure of alkaloid 228 isolated from Streptomyces rimosus.
Fig. 55. Structure of piperine alkaloid.
Fig. 56. Structure of chabamide isolated from Piper chaba.
Hirustellone D (221) were isolated from fungal species Hirustella
nivea BCC 2594 and exhibited significant antitubercular activity
against M. tuberculosis with inhibitory concentration of 0.78, 0.78,
0.78, and 3.125 mg/mL, respectively (Fig. 51) [337].
Through the extensive investigation of Serpula himantoids, fun-
gus found in Chile, four interesting alkaloids viz. himanimide A
(222), himanimide B (223), himanimide C (224), and himanimide D
(225) have been isolated successfully (Fig. 52). Among these alka-
loids himanimides C (224) was found more effective against
M. phlei with MIC value of 25 mg/mL [338].
Tetrameric acid analogue were isolated from Myeelia extract of
fungus Epicoccum sp. Epiccocarines A (226) and B (227) (Fig. 53)
possess antimycobacterial activity against M. vaccae with MIC value
of 6.25 mg/mL [339].
Similarly, fermentation of Streptomyces rimosus resulted a pro-
tein kinase inhibitor 228, which was also found as a potent anti-
mycobacterial agent against M. aurum and M. phlei at loading dose
of 20 mg/disc (Fig. 54) [340,341].
9.14. Piperidine alkaloid
Piperine (229), an analogue of 1-piperonyl piperidine, which
was isolated from Piper nigrum, exhibited the antimycobacterial
activity against M. smegmatis with MIC value of 128 mg/mL. Piperine
also inhibited the efflux pump (putative multidrug) M. Tb (Fig. 55)
Fig. 57. Structure of neopetrosiamine A.
 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544
Fig. 58. Structure of tetracyclic diamine alkaloids isolated from sea sponge Haliclona
sp.
[342].
Chemical investigation of Piper chaba stem resulted to the suc-
cessful isolation of methylene dioxybenzene analogue chabamide
(230), which possess antitubercular activity against M. tuberculosis
H37Ra strain with MIC value of 12.5 mg/mL (Fig. 56) [343].
In a research program, a series of interesting bis-piperidine
alkaloid and tetracyclic bis-piperidine alkaloids were isolated with
a purpose to find a potential lead molecule useful to cure tuber-
culosis. Thus, bis-piperidine alkaloid neopetrosiamine A (231),
isolated from sea sponge Neopetrosia proxima, possesses significant
antimycobacterial activity against M. tuberculosis with MIC value of
7.5 mg/mL (Fig. 57) [344].
Fractionation of sea sponge Haliclona sp. reported new tetra-
cyclic diamine alkaloid halicyclamine A (232) with MIC value
against M. tuberculosis (H37Ra) in between of 1.0e5.0 mg/mL
(Fig. 58) [345]. When tested against M. smegmatis and M. bovis
halicyclamine A, the observed MIC was 2.5 and 1.0 mg/mL, respec-
tively. Halicyclamine A has potent activity against M. tuberculosis,
which is resistant to isoniazid, ethambutol, rifampin and strepto-
mycin with MIC value of 3.13e6.25 mg/mL under aerobic conditions
[345].
Fig. 59. Structure of Cyclopeptide alkaloids.
531
Fig. 60. Structure of Agelasine alkaloids.
Furthermore, from the same species of Haliclona, a series of
similar alkylpiperidine-based alkaloids were isolated namely, 22-
dihydroxy haliclonacyclamine (233) and its analogue hal-
iclonacyclamines A (234) as well haliclonacyclamines B (235)
(Fig. 58), which has potent activity against Mycobacteria (M.smeg-
matis and M. bovis) in both condition i.e. aerobic and anaerobic with
inhibitory concentration of 12.5e25 mg/mL, 2.5 mg/mL and 1.0 mg/
mL, respectively. Haliclonacyclamines B has potency against both
active and dormant growing Mycobacteria [346,347].
9.15. Cyclopeptide alkaloids
Ziziphus mauritiana was reported to be rich in antimycobacterial
cyclopeptide alkaloids. Further investigation of the plant resulted to
the isolation of two cyclic alkaloids and three cyclopeptide alka-
loids. On biological screening, it was reported that cyclopeptide
alkaloid mauritine M (236) and nummularine H (237) were found
to moderately inhibition of M. tuberculosis (Fig. 59) [348].
9.16. Agelasine alkaloids
Marine sponge Agelas nakamurai has been reported with Age-
lasine E (238), which has found to be active against Mycobacterium
sp. This alkaloid and its analogues viz A (239), B (240), C (241), and
D (9-methyladenine) (242) have better antitubercular activity and
effective against H37Rv strain. The MIC value of compound 239, 240,
241, and 242 were found to be 3.13, 1.56, 3.0, and 6.25 mg/mL,
respectively [244,349,350]. Interestingly, another species of Agelas,
origin of Philippines, resulted an alkaloid Agelasine F (243) that
significantly retard the growth of M. tuberculosis H37Rv strain with
the MIC value of 3.13 mg/mL (Fig. 60) [351,352].
Synthetic analogue of agelasines and agelasimines for example,
compound 244 and 245 were found effective against M. tuberculosis
with an inhibitory concentration of 6.25 mg/mL [353]. O-Benzyl
532 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544

Fig. 61. Structure of agelasines and agelasimines analogues with antitubercular activity.

analogue 246 of agelasines showed 46% inhibition at the concen-
tration of 6.25 mg/mL, whereas agelasine D (247), compounds 248,
249, 250, 251 and N-alkoxy derivative 252 & 253 were known to
inhibits the M. tuberculosis with varying efficacy at the minimum
concentration of 6.25 mg/mL respectively (Fig. 61). Compound 253
has been recognized as the potent compound with MIC 3.13 mg/mL
against M. tuberculosis [354].
9.17. Polycyclic guanidine alkaloids
A series of interesting antimycobacterial polycyclic guanidine
alkaloids named batzelladine L (254), batzelladine M (255), bat-
zelladine N (256), batzelladine C (257), dehydrobatzelladine C (258)
and crambescidine 800 (259) has been isolated from Monanchora
unguifera, a marine sponge (Fig. 62) [355]. Among these alkaloids
batzelladine L and batzelladine N possess most satisfactory anti-
mycobacterial activity with MIC value of 1.68 and 3.18 mg/mL,
respectively. Batzelladine M, C, dehydrobatzelladine C and cram-
bescidine 800 exhibited mild activity against M. tuberculosis (H37Rv
strain) with MIC value of 28.5, 34.7, 37.7 and 46.5 mg/mL, respec-
tively. Among these guanidine alkaloids, ptilomycin A (260), 16b-
hydroxy-crambescidin (261) and compound 262 were not shown
any significant antitubercular activity [355].
9.18. Oxazole alkaloids
Benzoxazole alkaloids, obtained from marine metabolites of
Pseudopterogorgia elisabethae, are strong inhibitor of
M. tuberculosis. Pseudopteroxazole (263), seco-pseudopteroxazole
(264) and homopseudopteraoxazole (265) exhibited its anti-
mycobacterial activity with MIC value of 12.5, 12.5 and 12.5 mg/mL,
respectively (Fig. 63) [356e358].
Bicyclic nitroimidazo-oxazole (266) showed in vitro as well as
in vivo antimycobacterial activity and possess mutagenicity which
was later modified by substitution at 2nd position with 6-nitro-2,3-
dihydroimidazo [2,1-b]oxazole (267) with MIC value of 0.05 mg/mL
against M. tuberculosis H37Rv. Substitution with hydrophilic group
(268) increases the antitubercular activity against M. tuberculosis
H37Ra and H37Rv with inhibitory concentration of 0.78 and 0.39 mg/
mL, respectively whereas lipophilic group (269) substitution led to
most potent antimycobacterial compound against M. Tb H37Rv with
MIC of 0.006 mg/mL (Fig. 64) [359].
Texalin (270), a tetracyclic oxazole alkaloid isolated from Amyris
elemifera, inhibited M. tuberculosis, M. avium and M. kansasii with
MIC 25 mg/mL (Fig. 65) [360].
Transvalenein Z (271, Fig. 66), isolated from Nocardia trans-
valensis, was found to be effective against acid fast bacteria
M. smegmatis with MIC value of 0.125 mg/mL [361].
 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544 533

Fig. 62. Structure of polycyclic guanidine alkaloids.

9.19. Diterpenoid b-lactam alkaloids

Diterpenoid b-lactam alkaloid monamphilectine A (272) and

8,15-diisocyano-11 (20)-amphilectine (273) (Fig. 67) were isolated
from marine sponge Hymenia cidon, which showed potent anti-
mycobacterial properties with MIC value of 15.3 and 2.0 mg/mL
respectively [362].
Some 2-azetidinone derivatives known for their antitubercular
activity against M. tuberculosis H37Rv with 90% inhibition and then
after re-evaluated at lower concentration using BACTEC 460
compared with standard antimycobacterial rifampin at 0.031 mg/
mL [363]. 2,4-Dichlorophenyl or o-chlorophenyl substitution (274
and 275) increases antimycobacterial activity of 2-azetidinone
(Fig. 68) [363].
Furthermore, from a synthetic livbrary of azetidinone analogues
viz. 4-aryl-3-chloro-N-(3,4,5-trihydroxy benzamido)-2-
azetidinones (276a-o), compounds 276f, 276 g, 276 k and 276
showed potent antimycobacterial activity against M. tuberculosis
with MIC of 0.76, 0.57, 0.62 and 0.83 mg/mL, respectively. Chloro
(276f, g, o) and dimethyl amino (276 k) substitution in azetidinones
resulted in enhancement of antitubercular activity, while other
substitutions did not exhibit any remarkable antimycobacterial
activity. Substitution at m-position with chloro group indicated the Fig. 63. Structure of Benzoxazole alkaloids isolated from marine metabolites of Pseu-
dopterogorgia elisabethae.
534 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544

N
H

O
N

Cl
Ar
274: Ar = 2,4-dichlorophenyl
275: Ar = O-chlorophenyl

OH
276a: R= H 276h: R= 2-NO2
HO O
276b: 2-OH/R 276i: R= 3-NO2
NH N Cl 276c R = 2-OH-3-OCH3 276j: R= 4-NO2
HO 276d: R = 3-OH 276k: R= 4-N-(CH3)2
O 276e:R = 4-OH 276l: R= 3,4,5-(OCH3)3
276f: R = 2-Cl 276m:R = 3,4-(OCH3)2
276g: R = 3-Cl 276n: R= 4-OCH3
Fig. 64. Structure of nitroimidazo-oxazole analogues. 276 R 276o: R= Cl

Fig. 68. Structure of 2-azetidinone derivatives.

Fig. 65. Structure of tetracyclic oxazole alkaloid.

Fig. 69. Structure of pyridine N-oxide alkaloid.

Fig. 66. Structure of Transvalenein Z isolated from Nocardia transvalensis.

highest antitubercular activity in all the compounds. This was

envisaged that the introduction of electron withdrawing and bulky
group (such as dimethyl amino) has good inhibitory property
against tuberculosis and this has also been evidenced if incorpo- Fig. 70. Structure of alkaloids isolated from marine invertebrates.
ration of electron withdrawing group in the structure of simple
existing antitubercular drugs, like isoniazid and pyrizinamide is
considered [364]. MIC value of 1.25 mg/mL (Fig. 69) [365].
Streptomyces sp. is a good source of antibacterial alkaloids
among them one metabolite viz. metabolite-A has potent anti-
9.20. Miscellaneous alkaloids mycobacterial activity with MIC value of 10e14 mg/mL [366,367].
Screening of marine invertebrates has led to find new species
Allium stipitatum possess pyridine N-oxide (277) alkaloid, which Aplysina cauliformis and Pachychalina sp. which resulted to the
has significant anti-tuberculosis effect on H37Rv strain of M. Tb with

Fig. 67. Structure of diterpenoid b-lactam alkaloid analogues. Fig. 71. Structure of bis-1-oxaquinolizidine alkaloid from marine source.
 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544
Fig. 72. Brominated fistularin derived alkaloids possess antitubercular activity.
Fig. 73. Structure of (-)-deoxypergularinine.
isolation of two bioactive alkaloids 278 and 279 (Fig. 70). Com-
pound 278 was effective against M. tuberculosis H37Rv with MIC
value of 15.9 mg/mL, however compound 279 was not found
Fig. 74. Structure of dithioketopiperazines analogues from Meninsporopsis theobromae.
535
effective.
In another program, a very interesting alkaloid namly bis-1-
oxaquinolizidine was isolated from marine source. (þ)-Aragus-
pongine C (280) was isolated from the marine sponge Xestospongia
exigua, which showed to inhibit M. tuberculosis H37Rv with an MIC
of 1.9 mg/mL (Fig. 71) [368].
Brominated fistularin derivative 281 and 282 (Fig. 72), possess
promising activity against Mycobacteria with MIC value of 7.9 and
8.0 mg/mL, respectively [369].
The ethanolic extract of C. atratum was screened in n-hexane
and the dichloromethane and showed that (-)-Deoxypergularinine
(12.5 mg/mL) inhibited the growth of H37Ra M. Tb strain until 42
days, and also MICs of 12.5 mg/mL have been observed against six
M. tuberculosis strains namely H37Ra- M. Tb, H37Rv- M. Tb, MDR-
M. Tb, XDR-M. Tb, INH resistant M. Tb, and pyrazinamide resistant
M. Tb. Moreover, (-)-deoxypergularinine (283) (Fig. 73) with an MIC
of 6.25 mg/mL shown effectiveness against rifampicin-resistant TB
also against MDR/XDR strains, and harmonious effects with
rifampicin and isoniazid for the H37Ra strain [370,371]. The alkaloid
was considred as a potent drug for targeting M/XDR M. tuberculosis.
Meninsporopsis theobromae, seed fungus was reported with
dithioketopiperazines analogues 284, 285 and 286. These alkaloids
(284-286) were exhibited antimycobacterial activity against
M. tuberculosis H37Ra strain with MIC value of 100 mg/mL, 0.80 mg/
mL and 3.10 mg/mL, respectively (Fig. 74) [372].
10. Conclusion and future purspective
Despite the introduction of cheap and effective treatment with
quadruple drug therapy for tuberculosis, there is still urgency for
new better drugs, less toxic treatment regimens with shorter ways
of evaluating new TB drugs and regimens. We need improved di-
rections and strong collaborative network from all the researching
bodies, which are involved in drug discovery for TB. In same
aforesaid, we compiled the up to date TB research and introduced
the role of alkaloids in tuberculosis drug discovery. Moreover, there
is also need the improved tools for the detection of tuberculosis,
which can be use in laboratories to assist early case finding from the
populations.
Since very beginning, natural products alone or their derivatives
are considered as the most valuable source for the drug candidates
useful in the treatment of various diseases, and several groups have
536 S.K. Mishra et al. / European Journal of Medicinal Chemistry 137 (2017) 504e544

been actively involved to find a lead from natural sources to control PCR Polymerase Chain Reaction
tuberculosis. The review compiles literature up to 2016 as well as TB Tuberculosis
recent drugs of pipeline that may be natural, synthetic or semi HIV Human Immunodeficiency Virus
synthetic. This review covers the most active naturally occurring SAR Strucuture Activity Relationship
compounds with antitubercular properties at minimum inhibitory US FDA United States Food and Drug Administration
concentrations (MICs) of 50 mg/mL or less. The biological activity of WHO World Health Organization
natural products provides a hope for prompt discovery of highly MDR-TB Multi-drug resistant tuberculosis
effective low-toxic leads, which may be a potent drug to fight XDR-TB Extensively drug resistant tuberculosis
against tuberculosis. Some plant-derived alkaloids having MICs in TDR-TB/XXDR-TB Totally drug resistant/extremely drug resistant
range of 0.05 mg/mL are proving alkaloids as lead to answer the tuberculosis
community involved in search of therapeutic agents for treatment M.Tb Mycobacterium tuberculosis
of tuberculosis those are far from satisfaction so far. Extensive MIC Minimum inhibitory concentration
studies on the alkaloids having lower MICs can formulate a good mg Microgram
antituberculosis compound with benefit of fewer side effects. mL Millilitre
Moreover, these would serve as a useful scaffolds or templates mM Micromolar
for the development of new specific and selective anti- INH Isoniazid
mycobacterial drugs. Celastramycin A exhibited the MIC value of BACTEC Bactenecin
0.05e3.1 mg/mL against M. vaccae, M. fortuitum, M. smegmatis DCM Dichloromethane
strains, which is quite a potent MIC level and some synthetic sp Species
compounds like PA-824, SQ-109 etc are currently in phase II clinical pg Picogram
trials, and TMC-207, currently in phase III clinical trials, showed MIC NGO Non Governmental Organization
in the range of 0.015e0.03 mg/mL in vitro against M. tuberculosis CD4/8 Cluster of Differentiation-4/8
[264]. (-)-Deoxypergularinine with an MIC of 6.25 mg/mL is a potent TLR Toll Like Receptors
drug for targeting M/XDR M. tuberculosis. CNS Central Nervous System
Although considerable effort is needed to obtain new class of Fc-R Fragment Crystallizable Receptors
optimized and safe anti-tuberculosis agents from the natural AIDS Acquired Immunodeficiency Syndrome
product alkaloid family, evaluation for their antimycobacterial ac- NAD Nicotinamide adenine dinucleotide
tivity both, in vitro as well in vivo, identification of mechanisms of ACP Acyl Carrier Protein
action, their chemical and metabolic stabilities, pharmacokinetic DNA Deoxyribonucleic acid
studies to fight against tuberculosis [373]. Interestingly, ruthenium RNA Ribonucleic acid
complexes with some amino acids were developed evaluated rRNA Ribosomal Ribonucleic acid
against M. tuberculosis H37Rv where MIC values of the complexes mRNA Messenger Ribonucleic acid
are found to be comparable to the first-line drugs ethambutol (MIC DprE1 decaprenylphosphoryl-b-D-ribose oxidase
5.61 mg/mL) and second-line drug cycloserine (MIC 12.5e50.0 mg/ DOT Directly Observed Treatment
mL) requires more studies [374]. Similar investigation with library OECD Organization for Economic Co-operation and
of natural product inspired molecules especially alkaloids [375] Development
identified as the most active one should be strongly encouraged. dsDNA Double stranded deoxyribonucleic acid
Furthermore arising from the needs of biochemists (microbiologist dTMKase Thymidine monophosphate kinase
and molecular biologists), well-established rapid construction of DTDP Thymidine diphosphate
large collections of alkaloid related compounds under standard FAS Fatty acid synthase
coupling protocol [376] or cyclorelease strategy [377] on solid ICL Isocitrate lyase
support could be even more beneficial, although little attempt is ATP Adenine triphosphate
made in this direction [196,378]. The combined application of solid ATCC American Type Culture Collection
supported combinatorial chemistry and established diverse scaf- BCG Bacillus CalmetteeGue
rin
fold of identified potent antituberculosis alkaloids isolated in major NRA Nitrate reductase assay
amount from different natural resources, chemist may further IC50 Inhibitory Concentration
investigate to develop library of natural product inspired molecules NAATs Nucleic Acid Amplification Tests
first in mili gram scale to find out more potent molecule and then in SI Selectivity Index
gram scale using solution phase chemistry for complete pharma- HTS High-Throughput Screening
cological studies and thus could be considered a useful way to end CDC Centre for Disease Control
of with molecule useful to combat tuberculosis.

References
Acknowledgements
The authors thank Banaras Hindu University for all the support.
VKT gratefully acknowledge Department of Science & Technology
(DST), New Delhi for the DST fast track project for young scientist
(in 2006, Project No. M-48/73) and also Science Engineering and
Research Board (SERB), Department of Science & Technology, New
Delhi (in 2016, Grant No. EMR/2016/001123) for the funding.
Abbreviations
IFN-g Interferon-gamma
IGRAs Interferon-Gamma Release Assays
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