Indian Ayurvedic System of Medicine: Scope for

New Drug Design and Discovery

Dr. Narshinha P. Argade

Division of Organic Chemistry

National Chemical Laboratory, Pune 411 008
INDIA

np.argade@ncl.res.in
1
 Guru-Shishya Tradition

INDIA / CHINA

Dhanwantari: Physician of Gods 2

Saraswati: Godess of Knowledge Father and Promulgator of Ayurveda
Mother of Veda’s
World of Ayurveda: Rich Repository of Original Knowledge
™ Charak Samhita
™ Sushruta Samhita
™ Madhava Nidana
™ Astanga Haridaya

¾ Indian area: 2.4% of the world with range of geoclimatic conditions

¾ Indian biodiversity: 8.1% of the world
¾ Indian Plant Species: 45000 (3000 used in Ayurveda)
¾ Indian Ayurvedic formulations: 35000 + Bhasmas
¾ Indian Registered Ayurvedic Practitioners: 6,00,000 3
Development of Ayurvedic Formulations

™Observation
™Hypothesis formulation
™Testing by experiments
™Induction derived general principle
™Application of general principle

4
 Diseases and Ayurvedic Medicines

Disease Plant species Common name

Multiresistant Tuberculosis Cyperus rotundus Motha

Obesity & heart diseases Commiphora mukul Guggulu

Cancer Rubia cordifolia Manjistha

Diabetes Petrocarpus marsupium Vijaysar

Asthma Adhatoda vasica Adhulsa

Hepatitis Peganum nigellastrum Syrian rue

5
Comparison of Ayurvedic System of Medicine with Allopathy

Ayurvedic System Allopathic System

Experiential Experimental
Holistic Reductionistic
Philophical Physical
Health oriented Disease oriented
Diet oriented Drug and surgery oriented
Green pharmacy Red pharmacy
Pro-nature Anti-nature
Client oriented Profession oriented
Active on all humans Active on 30% humans
No side effects Side effects
Mode of action unknown Mode of action known ?
Slow effects Fast effects
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 Shri Zandu Bhattji
First Institute of Ayurvedic
Education: Gurukul Kangdi

Ayurvedic Colleges in India: 210

BAMS: 8000
MAMS: 600 “I Desire that the Diseases and
Miseries of all Living Beings are
Resolved ” 7
Natural Products Derived Drugs 1998-2004

8
 New Drug Discovery @ NCL
Natural Products
Extraction

Evaporation

Separation Assay
Development
Hits & Leads
High-Throughput
O
Screening
N
N
Parallel
OH
Synthesis
O New
N
H
N
O
N
HO
O
H
O
Drugs
O O
H
OH
HO
H
O
H
O
O
9
Synthetic Products
 Commiphora mukul

O
Dr. G. V. Satyavati
“1966-Guggulu Girl” Z-Guggulsterone
(Cholesterol Lowering Agent)
10
G. V. Satyavati et al. Ind. J. Med. Res. 1988, 87, 327.
 A Natural Product That Lowers Cholesterol As an
Antagonist Ligand for FXR
Nancy L. Urizar, Amy B. Liverman, DÕNette T. Dodds, Frank Valentin Silva,
Peter Ordentlich, Yingzhuo Yan, Frank J. Gonzalez, Richard A. Heyman, David
J. Mangelsdorf, David D. Moore*

¾ The gum resin of Commiphora mukul (guggulu in Sanskrit)

has been used in Ayurvedic medicine since at least 600 BC to
treat a wide variety of ailments, including obesity and lipid
disorders.

Science 2002, 296, 1703.

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 (-)-Vasicine, (-)-Vasicinone and Isovasicinone

N N

N N
OH OH
(-)-Vasicine (-)-Vasicinone

O OH

Isovasicinone

Isolation: Adhatoda vasica

Activity: Used in “The Indian Ayurvedic System of
Medicine” as a remedy for cough, cold and
bronchitis

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Earlier Approaches towards Vasicinone
O O

Davis reagent
N N
-78 oC
N N
OH
39% (71% ee)

Eguchi et al. J. Org. Chem. 1996, 61, 7316.

O O

Amano PS, VA
N N
THF
N N
OH OAc
45% (100% ee)

Kamal et al. J. Org. Chem. 2001, 66, 997.

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 NCL-Synthesis of (-)-Vasicinone

O O
CONH2 O OH CONH2 O OMe
NH2 Ether O CH2N2 O
+ O
(98%) (98%)
NH2 N N
OAc H H
O OAc OAc
4 5
2 3 (a) LAH
(b) H2O
(92%)
O O

DEAD, OH CONH2 OH
N TPP NH O

(90%)
N N N
H
OH OH OH
(-)-Vasicinone (1) 7 6

S. B. Mhaske and N. P. Argade J. Org. Chem. 2001, 66, 9038.

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 Synthesis of (-)-Vasicine - in Progress

NHBoc NHBoc
O
O OH O OMe
NHBoc Ether O CH2N2 O
+ O
(95%) (87%)
NH2 OAc N N
H H
O OAc OAc
2 3 4 5
LAH, THF
(73%)

NHBoc
OH OH
N ? NH TFA O
X
N N N
H
OH OH OH
(-)-Vasicine (1) 7 6

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 Naturally Occurring Luotonin Alkaloids
O R O
N
N NH
A B C
MeO N
N D N N
N E O
O
R'
Luotonin A: R = H Luotonin F
Luotonin B: R = OH Luotonin C (R' = Me)
Luotonin E: R = OMe Luotonin D (R' = Et)

Nomura et al. Heterocycles 1997, 46, 541.

Activity: Used in “The O N

A B C
Indian Ayurvedic D
O
System of Medicine” HO N E

as a remedy for
Camptothecin
hepatitis
Peganum nigellastrum
Human DNA topoisomerase inhibitor (leukemia P-388 cell line, IC50 1.8 μg/mL)
Hecht et al. JACS 2003, 125, 13628. 16
Earlier Approaches towards Luotonin A
O

N Aniline, Dy(OTf)3

H (51%)
N
1 O O

N
O
N
N N
H
N
N Ph3PO, Tf2O

2 O (99%)

Batey et al. Org. Lett. 2004, 6, 4913.

Yao et al. J. Org. Chem. 2007, 72, 6270.
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 An Efficient Biogenetic Total Synthesis of Luotonin F
O O
Et2O CONH2 CONH2
NH2 COOH CH2N2 COOMe
+ O O O
(98%) (98%)
NH2 N N
O H H
1 3 4
2
(i) LAH/THF
(ii) H2O
O O
CHO PCC OH CONH2 OH
NH NH O
(64%)
N N N
[6] H
Pegamine (93%) [5]

O OH o-Amino- O O
benzaldehyde, N
N N CrO3/H5IO6
KOH NH NH
N (62%) (96%)
N N
Isovasicinone (7) O
Deoxoluotonin F (8) Luotonin F

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 Practical Synthesis of Luotonin A and Luotonin B & E via
Novel ortho-Directed Lithiation
O O
CONH2
NH2 i O ii NH 3`
+
Cl (96%) (98%)
NH2 N N N
H 8
O N N
2 3 4 5
8`
iiia

O O OH O
Li
N iv NH iiib NLi
(95%) (86%)
N N N
N N N
Luotonin A (1a) 7 [6]
v (61%) iiic (81%)

O OMe O OH O
CHO
N vi N NLi
(82%)
N N N
N N N
Luotonin E (1c) Luotonin B (1b) [8]

Reagents,condition and Yields: (i) TEA (2 eq.), THF, rt, 3 h (96%); (ii) 5% aq. KOH, EtOH, reflux, 5 min. (98%); (iiia) Mesityl
lithium (2.2 eq.), − 78 oC, 1 h to − 20 oC (gradually), (iiib) THF solution of HCHO (5 eq.), − 30 oC, 20 min., saturated aq. solution of
NH4Cl (86%), (iiic) DMF (5 eq.), − 20 oC, 30 min., saturated aq. solution of NH4Cl (81%); (iv) PPh3 (1.3 eq.), DEAD (1.2 eq.), THF,
rt, 1 h (95%); (v) PCC (1.2 eq.), powdered 4Å molecular sieves, DCM, rt, 1 h (61%); (vi) p-TSA (5 eq.), MeOH, reflux, 3 h (82%).
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S. B. Mhaske and N. P. Argade J. Org. Chem. 2004, 69, 4563.
 Synthesis of Luotonins C, in Progress

NH2 + O
HN O
MeO N MeO N
CH3 H
H
O HOOC
2 3 4
CH3

N
N MeO
N
MeO N MeO N N
H
HOOC
O
O
CH3 CH3
CH3
5 6 Luotonin C (1)

P. B. Wakchaure and N. P. Argade (Unpublished results).

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 Indian Ayurvedic
Chemist Doctor
System of Medicine

Safe but slow Fast and more

safe

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 Acknowledgements

Dr. S. B. Desai Aquapharm Ltd., Pune

Dr. A. M. Deshpande Recon Ltd., Bangalore
Dr. S. Mangaleswaran
Godrej Agrovet, Mumbai
Dr. S. B. Mhaske
Dr. Anirban Kar Parke-Davis, USA
Dr. S. Easwar Yamanuchi, Japan
Dr. M. Mondal Nikem, Italy
Dr. Merajuddin Baag DST, New Delhi
Dr. Sanjib Gogoi
CSIR, New Delhi
Mr. Kishan Haval (SRF)
Mr. Umesh Kshirsagar (SRF) ICS-UNIDO, Italy
Mr. Ramesh Patel (SRF) Dr. G. P. Pandey, Head
Mr. Prasad Wakchaure (SRF) DOC, NCL, Pune
Mr. Mandeep Singh (JRF) Dr. S. Sivaram, Director
Mr. Prashant Deore (JRF) NCL, Pune, India 22
The purpose of this laboratory is to advance knowledge
and apply chemical science for the good of the people

National Chemical Laboratory, Pune, India

www.ncl-india.org

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Thank You

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