Summary,of Ph.

D thesis
Introduction
In an era of increasing bacterial resistance to classical antibacterial agents, it has been
postulated that the development of resistance to known antibiotics could be overcome by
identifying new drug targets via genomic, improving existing antibiotics and most
importantly by identifying the new antibacterial agents with novel structures and mode
of action (Salahuddin et al., 2009). Non-sterile products such as pharmaceuticals,
cosmetics, food items etc. with a high degree of water availability may be contaminated
with microorganisms which may cause spoilage of the product with loss of therapeutic
properties and, if they are pathogenic, serious infections can arise (Zani et al., 1997). To
inhibit the growth of contaminating microorganisms, antimicrobial preservative systems
have been developed and introduced into the pharmaceutical, cosmetic or food products
during manufacturing process and/or throughout its use by consumers (Denyer et al.,
1988).
The commonly used chemical preservatives may cause very serious side effects. For
example, benzalkonium chloride may cause mucosal damage and was also reported as
genotoxic and cytotoxic (Deutschle et al., 2006 and Graf, 2006); thiomerosal used in
ocular and nasal preparations was reported to be cytotoxic by Liao et al. (2011), the use
of parabens may cause skin cancer, genotoxicity and breast cancer as reported by the
study of Dabre and Harvey (2008).
In several cases, the microorganisms become resistant to antimicrobials and are able to
degrade many commonly used preservatives especially p-hydroxybenzoates, e.g.,
parabens (Close and Nielsen, 1976). Microbial resistance has been reported to some of
the existing commonly used chemical preservatives like benzalkonium chloride,
dibromodicyanobutane,

chloramine, chlorhexidine, cholorophenol, benzoic acid,

dimethyl oxazolidine, dimethyl dithiocarbamate, dimethoxy dimethyl hydantoin,

formaldehyde, glutaraldehyde, hydrogen peroxide, iodine, methylene bischlorophenol,
methylparaben, propylparaben, phenylmercuric acetate, mercuric salts, povidine-iodine,
sorbic acid and quaternary ammonium compounds (Chapman, 1998).
The antimicrobial potential of simple organic acids is well established in the literature viz.
sorbic acid (Nararasimhan et al., 2003), cinnamic acid (Narasimhan et al., 2004), anacardic
acid (Narasimhan et al., 2006a), veratric acid (Narasimhan et al., 2009), myristic acid
Development and evaluation of novel preservatives from simple organic acids
i

Summary,of Ph.D thesis

(Narasimhan et al., 2006b), caprylic acid (Chaudhary et al., 2008), anthranilic acid (Mahiwal
et al., 2012) and dodecanoic acid (Sarova et al., 2011).
Further, the literature reports reveals that the ferulic acid possess antimicrobial,
antioxidant and preservative activities (Proestos et al., 2006 and Ou et al., 2004). The
gallic acid and its derivatives possess wide spectrum of biological activities like
antimicrobial, anticancer, antiviral, anti-inflammatory, analgesic and anti-HIV activities
(Chanwitheesuk et al., 2007; Saxena et al., 2008; Thapa et al., 2012; Arunkumar et al.,
2009; Krogh et al., 2000 and Kratz et al., 2008). Also, the p-coumaric acid and its
derivatives possess wide spectrum of biological activities like antimicrobial and
antioxidant potentials (Proestos et al., 2006 and Caia et al., 2004). Hence, the present
research work was envisaged towards development and evaluate the novel preservatives
from simple organic acids.
Objective
Development and evaluation of novel preservatives from simple organic acids.
Plan of work
In light of abovementioned facts and with the aim of obtaining new antimicrobial
preservatives, the present work was planned as follows:
I.

Synthesis of organic acid derivatives.

II.

Physicochemical and spectral characterization of synthesized compounds

III.

Evaluation of antimicrobial activity of synthesized compounds.

IV.

Preservative efficacy testing of selected antimicrobial agents in

pharmaceutical products as per USP guidelines.

V.

Stability studies of pharmaceutical products containing the test

preservatives as per ICH guidelines.

The aforementioned plan of work is executed as follows:

I.

A review of literature regarding the problems associated with the existing

chemical preservatives and their alternatives.

II.

Synthesis and antimicrobial evaluation of ferulic acid derivatives (Series I).

III.

Synthesis, antimicrobial evaluation and QSAR studies of gallic acid

derivatives (Series II).

Development and evaluation of novel preservatives from simple organic acids

ii

Summary,of Ph.D thesis

IV.

Synthesis, antimicrobial evaluation and QSAR studies of p- coumaric acid

derivatives (Series III).

V.

Evaluation of preservative effectiveness of ferulic acid derivatives in

aluminium hydroxide gel- USP

VI.

Evaluation of preservative effectiveness of gallic acid derivatives in

aluminium hydroxide gel- USP

VII.

Evaluation of preservative effectiveness of p- coumaric acid derivatives in

aluminium hydroxide gel- USP

VIII. Stability studies of the selected derivatives of ferulic acid, gallic acid and
p- coumaric acid as per the ICH guidelines.
I.

A review of literature regarding the problems associated with the existing chemical
preservatives and their alternatives.

Preservatives are very essential ingredient among the food and pharmaceutical products as
chances of contamination of such products is very high and their shelf life becomes short.
However, the preservatives which are used for this purpose may pose several serious
complications such as the benzalkonium chloride may cause nasal mucosal damage and
genotoxicity, thiomerosal may cause neonatal neurodevelopmental disorders, and parabens
may cause skin cancer, genotoxicity and breast cancer. So, the use of preservatives becomes
a challenge and there is a strong need to overcome these problems by finding alternatives to
existing preservatives. This includes the use of novel preservatives such as polyquad, sodium
perborate, purite, sofZia etc. or use of speciallized packaging or exploration of novel
antimicrobial preservatives from natural acids.
Publication from aforementioned work
Khatkar A, Nanda A, Narasimhan B. Preservatives- associated problems and possible
alternatives, in: Tiwari SK, Singh B (Eds.), Current Trends in Biotechnology, Lambert
Academic Publisher, Germany, 2012: 100-120.
II.

Synthesis and antimicrobial evaluation of ferulic acid derivatives (Series I).

A series of ferulic acid derivatives (1-38) was synthesized and characterized by

physicochemical and spectral means (Scheme 1). The synthesized compounds were
evaluated in vitro for their antimicrobial activity against different Gram positive and Gram
negative bacterial as well fungal strains by tube dilution method. Results of antimicrobial
Development and evaluation of novel preservatives from simple organic acids
iii

Summary,of Ph.D thesis

screening indicated that compound 1 was the most active antimicrobial agent (pMICam = 1.83
M/ml). The structural requirements for the antimicrobial activity of synthesized compounds
are summarized in Fig. 1.
H3CO

COOH

R-OH H3CO
H2SO4

HO

HO

CO

HO

R-OH
H3CO

HO
9, 12, 13

SOCl2
H3CO

COOR

H3CO

COOR

COCl
HO

N
HO

1, 3-8, 10, 11, 14

2
O
H3CO

H3CO

CONHR

HO

NH

HO

33, 35, 36, 38

34

2
NH
R-

H2N

H3CO
H3CO

COOH

COCl

HN
O

SOCl2
HO

CO
N
O

HO
NH2

HO

H3CO

R7

37
R3

R6

R4
R5
R3

H3CO
HO

R4

H
CO N
15-32

R5
R7

R6

Scheme 1. Scheme for the synthesis of ferulic acid derivatives (Series I)

Development and evaluation of novel preservatives from simple organic acids
iv

Summary,of Ph.D thesis

Comp.

Comp.

NH2

R
.

Comp.

CH3
.

10
.

C4H9

13

C3H7

11

NO2

C2H5

12

14

Comp.

R3

R4

R5

R6

R7

15

16

CH3

NO2

17

Cl

NO2

18

Cl

19

Cl

20

CH3

21

OCH3

22

CH3

CH3

23

CH3

CH3

24

CH3

CH3

25

NO2

Comp.

R3

R4

R5

R6

R7

Development and evaluation of novel preservatives from simple organic acids

v

Summary,of Ph.D thesis

26

NO2

27

NO2

28

CH3

Cl

CH3

31

OCH3

32

29
-

30

33

34

35

C3H7

36

C4H9

37

38

H3CO

O
C N

Morpholine

Increased antibacterial
activity against E. coli

HO

H3CO
HO

COOH

H3CO

COOR
NH2

Increased antimicrobial activity against

S. aureus, C. albicans and A. niger

HO

R
H3CO

CONH

Anilides

Do not showed the antimicrobial

activity against microbial strains

HO

Figure 1. Structural requirements for the antimicrobial activity of ferulic acid derivatives
Development and evaluation of novel preservatives from simple organic acids
vi

Summary,of Ph.D thesis

Publication from aforementioned work
Anurag Khatkar, Arun Nanda, Pradeep Kumar, Balasubramanian Narasimhan. Synthesis
and antimicrobial evaluation of ferulic acid derivatives. Research on Chemical
Intermediates (Communicated).
III.

Synthesis, antimicrobial evaluation and QSAR studies of gallic acid

derivatives

(Series II)
A series of gallic acid derivatives (1-33) was synthesized and characterized by
physicochemical and spectral means (Scheme 2). The synthesized compounds were
evaluated in vitro for their antimicrobial activity against different Gram positive and
Gram negative bacterial as well fungal strains by tube dilution method. Results of
antimicrobial screening indicated that compound 6 was the most active antimicrobial
agent (pMICam = 1.92 M/ml). The structural requirements for the antimicrobial and
anticancer activities of synthesized compounds are summarized in Fig. 2. The results of
QSAR studies demonstrated that antibacterial, antifungal and overall antimicrobial
activity of synthesized gallic acid derivatives was governed by the electronic parameters,
cosmic total energy (Cos E) and nuclear energy (Nu. E).
O

HO
N
HO

Increased antimicrobial activity

against C. albicans and E. coli

COOR

HO
HO
HO
HO
HO
HO

CON

Di-phenyl group

R1
R2

Di-methyl group

HO

Increased antibacterial
activity against B. subtilis
Increased antifungal
activity against A. niger

COOH
HO
HO

CONH

Increased antibacterial
activity against S. aureus

HO
Anilides

Figure 2.

Less active antimicrobial agents

Structural requirements for the antimicrobial activity of synthesized

gallic acid derivatives (Series III)
Development and evaluation of novel preservatives from simple organic acids
vii

Summary,of Ph.D thesis

HO

HO
R-OH

HO

COOH
H2SO4

HO

HO

COOR

HO

12, 22

SOCl2
HO

OH

HO

HO

O
C

R-OH

OH

HO

COCl

HO

COOR

O
OH

HO

HO
3-5, 10, 19, 23-24, 26, 32

HO

HO

HO
HO

CO NHR

H
CO N

HO

7, 20-21

HO
33

N
RH2

H2N
O
HO

HO
SOCl2
HO

HO

COOH

HO

N
H

HO

COCl

CO N
O

HO

HO

HO

18

NH2
R3

R7
NH
R

R6

HO
HO
HO

R1
CO N
R2
2, 13, 30

R4
R5

HO
HO
HO

R3
CO

H
N

R4
R5

R7
R6
1, 8, 9, 11, 14-17, 25, 27-29, 31

Scheme 2. Scheme for the synthesis of gallic acid derivatives (Series II)
Development and evaluation of novel preservatives from simple organic acids
viii

Summary,of Ph.D thesis

Comp.
3

R
.

NO2

Comp.
10

12

19

Comp.
23

R
.

CH3

26

C2H5

22

24

32

NH2

Comp.

R1

R2

R3

R4

R5

R6

R7

Cl

CH3

CH3

CH3

11

NH2

14

CH3

NO2

15

NO2

16

Cl

NO2

17

NO2

18

25

OCH3

27

NO2

28

Cl

Cl

29

Cl

Cl

31

NO2

Cl

Development and evaluation of novel preservatives from simple organic acids

ix

Summary,of Ph.D thesis

Comp.
2
7
13
20

R
C6H13
.

21

O
.

R1
CH3
C6H5
-

R2
CH3
C6H5
-

R3
-

R4
-

R5
-

R6
-

R7
-

C2H5
-

C2H5
-

30
33

LR-mt-QSAR model for antimicrobial activity

pMICam = 0.0000211 Nu. E + 1.033
n = 23

r = 0.848

q2 = 0.671

Eq. 1
s = 0.054

F = 53.57

Research article communicated from aforementioned work

Anurag Khatkar, Arun Nanda, Pradeep Kumar, Balasubramanian Narasimhan. Synthesis,
antimicrobial evaluation and QSAR studies of p- coumaric acid derivatives. Arabian
Journal of Chemistry (Communicated).
IV.

Synthesis, antimicrobial evaluation and QSAR studies of p- coumaric acid

derivatives (Series III)

A series of p- coumaric acid derivatives (1-36) was synthesized and characterized by

physicochemical and spectral means (Scheme 3). The synthesized compounds were
evaluated in vitro for their antimicrobial activity against different Gram positive and
Gram negative bacterial as well fungal strains by tube dilution method. Results of
antimicrobial screening indicated that compound 17 was the most active antimicrobial
agent (pMICam = 1.73 M/ml). The structural requirements for the antimicrobial activities
of synthesized compounds are summarized in Fig. 3. The mt-QSAR model of
antimicrobial activity (Eq. 2) depicted the importance of topological parameter, Wiener
index (W) in describing antimicrobial activity of synthesized compounds.
Development and evaluation of novel preservatives from simple organic acids
x

Summary,of Ph.D thesis

COOH

COOR

R-OH
H2SO4

HO

10, 23, 24

HO

SOCl2
CO

HO

COCl

HO

HO

COOR

R-OH

1, 11, 18-22, 25-26

HO
17

O
CONHR
HO

NH
HO

2, 4, 5

2
NH
R-

CO N
O
HO

30

H2N

O
HN

COCl
COOH

HN
CO

SOCl2

HO

HO
NH2

HO

34
R3

R6

NH
R

R7

R4
R5
R3

R1
CO N
R2
HO

8, 16, 29, 35

CO
HO

H
N

R4
R5

R7
R6
6, 7, 9, 12-15, 27-28, 31-33, 36

Scheme 3. Scheme for the synthesis of p- coumaric acid derivatives (Series III)

Development and evaluation of novel preservatives from simple organic acids

xi

Summary,of Ph.D thesis

Comp.

Comp.
18

C3H7

10
11

26

Comp.

R
.

22

C4H9

19
NH2

17

20

23

C2H5

24

CH3

21

25

NO2

Comp.

R1

R2

R3

R4

R5

R6

R7

Cl

NO2

OCH3

NO2

12

Cl

Cl

13

NO2

14

CH3

NO2

15

NH2

27

NO2

28

Cl

31

Cl

NO2

Development and evaluation of novel preservatives from simple organic acids

xii

Summary,of Ph.D thesis

Comp.

R1

R2

R3

R4

R5

R6

R7

32

Cl

33

36

CH3

CH3

C6H13

.
O

C2H4OH C2H4OH

16

C4H9

C4H9

29

C6H5

C6H5

30

34

35

CH3

CH3

O
N

Increased antibmicrobial activity

against S. aureus, C.albicans, A.niger

COOR
HO

Increased antimicrobial activity

against S. aureus
O
C N R1
R2

Diphenyl amine

Increased antimicrobial activity against

E.coli

HO
COOH
Cl

HO
COOR

NO2
HO

R
CONH

Anilides

Increased antibmicrobial activity

against B.subtilis

Electron withdrawing substituents

increased antimicrobial activity
against E.coli

HO

Figure 3. Structural requirements for antimicrobial activity of p- coumaric acid derivatives

Development and evaluation of novel preservatives from simple organic acids
xiii

Summary,of Ph.D thesis

LR mt-QSAR model for antimicrobial activity
pMICam = 0. 000312 W + 1.016
n = 32

r = 0.823

Eq. 2
q2 = 0.635

s = 0.065

F = 62.98

Publication from aforementioned work

Anurag Khatkar, Arun Nanda, Pradeep Kumar, Balasubramanian Narasimhan. Synthesis,
antimicrobial evaluation and QSAR studies of p- coumaric acid derivatives. Arabian
Journal of Chemistry (Communicated).
V.

Evaluation of preservative effectiveness of ferulic acid derivatives in aluminium

hydroxide gel- USP

The ferulic-p-amino ester, ferulic-morpholino amide, ferulic 8-hydroxy quinoline ester,

ferulic naphthyl amide were subjected to preservative efficacy testing in an official antacid
preparation (Aluminium Hydroxide Gel-USP) against Staphylococcus aureus, Bacillus
subtilis, Escherichia coli, Candida albicans and Aspergillus niger as representative
challenging microorganisms as per USP 2004 guidelines. The selected derivatives were
found to be effective against all selected strains and showed preservative efficacy comparable
to that of standard and even better in case B. subtilis and C. albicans. The 8- hydroxy
quinoline ester of ferulic acid showed better preservative efficacy than standard as well as
other derivatives and has the potential to be used as preservative in the pharmaceutical
preparations.
Publication from aforementioned work
Anurag Khatkar, Arun Nanda, Balasubramanian Narasimhan. Evaluation of preservative
effectiveness of ferulic acid derivatives in aluminium hydroxide gel- USP. International
Journal of Pharmaceutical Science and Research (Accepted).
VI.

Evaluation of preservative effectiveness of gallic acid derivatives in aluminium

hydroxide gel- USP
The selected amide, anilide and ester derivatives of gallic acid were subjected to

preservative efficacy testing in an official antacid preparation, (Aluminium Hydroxide GelUSP) against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Candida albicans
and Aspergillus niger as representative challenging microorganisms as per USP 2004
guidelines. The selected derivatives were found to be effective against all selected strains
Development and evaluation of novel preservatives from simple organic acids
xiv

Summary,of Ph.D thesis

and showed preservative efficacy comparable to that of standard and even better in
case E.coli, C. albicans and A.niger. The 8- hydroxy quinoline ester of gallic acid showed
better preservative efficacy than standard as well as other tested derivatives and have
potential to be used as preservative in the pharmaceutical preparations.
Publication from aforementioned work
Anurag Khatkar, Arun Nanda, Balasubramanian Narasimhan. Evaluation of preservative
effectiveness of gallic acid derivatives in aluminium hydroxide gel- USP. Chronicles of
Young Scientists (Accepted).
VII.

Evaluation of preservative effectiveness of p- coumaric acid derivatives in

aluminium hydroxide gel- USP

The selected amide (N,N-diphenyl amide and naphthyl amide), anilide (3-chloro 4-nitro
anilide) and ester (8-hydroxy quinoline ester) derivatives of p-coumaric acid were subject
to preservative efficacy testing in an official antacid preparation, (Aluminium Hydroxide
Gel-USP) against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Candida
albicans and Aspergillus niger as representative challenging microorganisms as per USP
2004 guidelines. The selected derivatives were found to be effective against all selected
strains and showed preservative efficacy comparable to that of standard and even better
in case E.coli, C. albicans and A.niger. The 8- hydroxy quinoline ester of p- coumaric
acid showed better preservative efficacy than standard as well as other derivatives and
have potential to be used as preservative in the pharmaceutical preparations.
Publication from aforementioned work
Anurag Khatkar, Arun Nanda, Balasubramanian Narasimhan. Evaluation of preservative
effectiveness of ferulic acid derivatives in aluminium hydroxide gel- USP. Chronicles of
Young Scientists (Accepted).
VIII.

Stability studies of the selected derivatives of ferulic acid, gallic acid and pcoumaric acid as per the ICH guidelines.

Samples of aluminium hydroxide gel containing the selected amide, anilide and ester
derivatives of ferulic acid, gallic acid and p- coumaric acid as preservative were stored at
400 20 C at 75% RH 5% RH (as per ICH guidelines) and were analyzed for the pH
and cfu/ml of the product at 0, 1, 2, 3, 4, 5 and 6 months. The results indicated that the
change in pH was comparable to that of standard and the microbial growth was observed
Development and evaluation of novel preservatives from simple organic acids
xv

Summary,of Ph.D thesis

in samples containing the preservatives gallic N,N-dimethyl amide, gallic naphthyl
amide, p- coumaric N,N-diphenyl amide, ferulic naphthyl amide, p- coumaric -2-chloro
4-nitro anilide, ferulic morpholino amide and p- coumaric naphthyl amide in last two
months. No microbial growth in samples of aluminium hydroxide gel containing the 8
hydroxy quinoline derivative of gallic acid, p- coumaric acid and ferulic acid and the pamino ester derivative of ferulic acid was observed and hence these derivatives were
stable over a period of six months and can be used as an alternative to the existing
chemical preservatives.
Publication from aforementioned work
Anurag Khatkar, Arun Nanda, Balasubramanian Narasimhan. Stability studies of the
selected derivatives of ferulic acid, gallic acid and p- coumaric acid as per the ICH
guidelines. HYGEIA: Journal of Drugs and Research (Communicated).
Conclusion:
Summarizing, the amide, anilide and ester derivatives of ferulic acid, gallic acid and pcoumaric acid were synthesized and evaluated for their in vitro antimicrobial activity and
the most active compounds were further evaluated for their preservative efficacy. The
results showed that the 8-hydroxy quinoline ester of ferulic, gallic and p-coumaric acids
were found to be effective during the preservative efficacy testing as well during the
stability studies as per the ICH guidelines.
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xviii