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Summary,of Ph.D thesis
Development and evaluation of novel preservatives from simple organic acids i
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
Summary,of Ph.D thesis
Development and evaluation of novel preservatives from simple organic acids ii
(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).
Summary,of Ph.D thesis
Development and evaluation of novel preservatives from simple organic acids iii
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
Summary,of Ph.D thesis
Development and evaluation of novel preservatives from simple organic acids iv
screening indicated that compound 1 was the most active antimicrobial agent (pMICam = 1.83
µM/ml). The structural requirements for the antimicrobial activity of synthesized compounds
are summarized in Fig. 1.
HO
COOH R-OH
H2SO4 HO
COOR
SOCl2
HO
COClR-OH
HO
COOR
N
HO
HO
CO
N
O
HO
COOH HO
COCl
SOCl2
HN
O
HO
CON
O
NH2
R7
R6
R5
R4
R3
HN
R7 R6
R5
R4R3
HO
CO
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
H3CO
HO
CONHRH3CO
37
R-N
H2
H2N
NH
HO
H3CO
O
34
2
9, 12, 13
1, 3-8, 10, 11, 14
33, 35, 36, 38
15-32
Scheme 1. Scheme for the synthesis of ferulic acid derivatives (Series I)
Summary,of Ph.D thesis
Development and evaluation of novel preservatives from simple organic acids v
Comp. R Comp. R Comp. R
1 NH2
5 .
9 CH3
2 - 6
.
10
.
3 .
7 NO2
.
11
.
4 C4H9 8 .
12 C2H5
13 C3H7 14
.
Comp. R R3 R4 R5 R6 R7
15 - H H H H H
16 - CH3 H H NO2 H
17 - Cl H NO2 H H
18 - H Cl H H H
19 - Cl H H H H
20 - H CH3 H H H
21 - OCH3 H H H H
22 - CH3 CH3 H H H
23 - CH3 H CH3 H H
24 - CH3 H H CH3 H
25 - NO2 - - - -
Comp. R R3 R4 R5 R6 R7
Summary,of Ph.D thesis
Development and evaluation of novel preservatives from simple organic acids vi
26 - H H NO2 H H
27 - H NO2 H H H
28 - CH3 H H H H
29 H Cl F H H
30 - H H CH3 H H
31 H H OCH3 H H
32 F H - H H
33 .
- - - - -
34 - - - - - -
35 C3H7 - - - - -
36 C4H9 - - - - -
37 - - - - -
38 N
O
.
- - - - -
HO
COOH
MorpholineIncreased antibacterial activity against E. coli
Increased antimicrobial activity against S. aureus, C. albicans and A. niger
HO
C
HO
COOR
HO
CONH
R Anilides Do not showed the antimicrobial activity against microbial strains
H3CO
H3CO
H3CO
H3CO
O
N O
NH2
Figure 1. Structural requirements for the antimicrobial activity of ferulic acid derivatives
Summary,of Ph.D thesis
Development and evaluation of novel preservatives from simple organic acids vii
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 µM/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).
HO
HO
HO
COOH
Anilides
HO
HO
HO
COOR
O
NIncreased antimicrobial activityagainst C. albicans and E. coli
HO
HO
HO
CONR1
HO
HO
HO
CONH R
R2
Less active antimicrobial agents
Di-phenyl group Increased antibacterial activity against B. subtilis
Di-methyl group Increased antifungal activity against A. niger
Increased antibacterial activity against S. aureus
Figure 2. Structural requirements for the antimicrobial activity of synthesized
gallic acid derivatives (Series III)
Summary,of Ph.D thesis
Development and evaluation of novel preservatives from simple organic acids viii
HO
HO
HO
COOHR-OH
H2SO4
HO
HO
HO
COOR
SOCl2
HO
HO
HO
COClR-OH
HO
HO
HO
COOR
HO
HO
HO
COOHSOCl2
HO
HO
HO
COCl
R-N
H2
HO
HO
HO
CO NHR
NHR 1
R 2
HO
HO
HO
CO N
R1
R2
NH2
R7
R6
R5
R4
R3
HO
HO
HO
COHN
R7 R6
R5
R4R3
N
HO
OH
OH
OH
C
O
O
N
12, 22
3-5, 10, 19, 23-24, 26, 32
6
H2N
HO
HO
HO
COHN
.
33
1, 8, 9, 11, 14-17, 25, 27-29, 31
2, 13, 30
7, 20-21
O
NH
HO
HO
HO
CO N
O
18
Scheme 2. Scheme for the synthesis of gallic acid derivatives (Series II)
Summary,of Ph.D thesis
Development and evaluation of novel preservatives from simple organic acids ix
Comp. R Comp. R Comp. R
3 NO2
.
10
.
23 .
4 .
12 CH3 24 .
5
.
19 .
26 .
6 - 22 C2H5 32
NH2
Comp. R R1 R2 R3 R4 R5 R6 R7
1 - - - H H Cl H H
8 - - - CH3 H CH3 H H
9 - - - H H CH3 H H
11 - - - NH2 H H H H
14 - - - CH3 H H NO2 H
15 - - - H H NO2 H H
16 - - - Cl H NO2 H H
17 - - - H NO2 H H H
18 - - - - - - - -
25 - - - H H OCH3 H H
27 - - - NO2 H H H H
28 - - - H Cl Cl H H
29 - - - Cl Cl H H H
31 - - - H NO2 Cl H H
Summary,of Ph.D thesis
Development and evaluation of novel preservatives from simple organic acids x
Comp. R R1 R2 R3 R4 R5 R6 R7
2 - CH3 CH3 - - - - -
7 C6H13 - - - - - - -
13 - C6H5 C6H5 - - - - -
20 N
.
O
- - - - - - -
21 .
O
- - - - - - -
30 - C2H5 C2H5 - - - - -
33 - - - - - - - -
LR-mt-QSAR model for antimicrobial activity
pMICam = 0.0000211 Nu. E + 1.033 Eq. 1
n = 23 r = 0.848 q2 = 0.671 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 µM/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.
Summary,of Ph.D thesis
Development and evaluation of novel preservatives from simple organic acids xi
HO
COOH R-OH
H2SO4 HO
COOR
SOCl2
HO
COClR-OH
HO
COOR
N
HO
HO
CO
N
O
HO
COOH HO
COCl
SOCl2
HN
O
HO
CON
O
NHR 1
R 2
NH2
R7
R6
R5
R4
R3
HN
R7 R6
R5
R4R3
HO
CO N
R2
R1
HO
CO
34
17
HO
CONHRR-N
H2
H2N
NH
HO
O
302, 4, 5
10, 23, 24
1, 11, 18-22, 25-26
8, 16, 29, 35 6, 7, 9, 12-15, 27-28, 31-33, 36
O
HN
HO
CO N
O3
Scheme 3. Scheme for the synthesis of p- coumaric acid derivatives (Series III)
Summary,of Ph.D thesis
Development and evaluation of novel preservatives from simple organic acids xii
Comp. R Comp. R Comp. R
1 .
18 .
22 .
10 C3H7 19 C4H9 23 C2H5
11 NH2
20
.
24 CH3
17 - 21 .
25 NO2
.
26 .
Comp. R R1 R2 R3 R4 R5 R6 R7
3 - - - - - - - -
6 - - - H Cl NO2 H H
7 - - - OCH3 H H H H
9 - - - NO2 H H H H
12 - - - H Cl Cl H H
13 - - - H H NO2 H H
14 - - - CH3 H H NO2 H
15 - - - NH2 H H H H
27 - - - H NO2 H H H
28 - - - H H Cl H H
31 - - - Cl H NO2 H H
Summary,of Ph.D thesis
Development and evaluation of novel preservatives from simple organic acids xiii
Comp. R R1 R2 R3 R4 R5 R6 R7
32 - - - H Cl H H H
33 - - - H H H H H
36 - - - CH3 H CH3 H H
2 C6H13 - - - - - - -
4
O
.
- - - - - - -
5 N
.
O
- - - - - - -
8 - C2H4OH C2H4OH - - - - -
16 - C4H9 C4H9 - - - - -
29 - C6H5 C6H5 - - - - -
30 - - - - - - - -
34 - - - - - - - -
35 - CH3 CH3 - - - - -
HO
COOH
O
NIncreased antibmicrobial activityagainst S. aureus, C.albicans, A.niger
Diphenyl amineIncreased antimicrobial activity against E.coli
HO
COOR
HO
C
HO
COOR
HO
CONH
R Anilides Electron withdrawing substituents increased antimicrobial activityagainst E.coli
O
N
NO2
Increased antimicrobial activityagainst S. aureus
Increased antibmicrobial activityagainst B.subtilis
Cl
R1
R2
Figure 3. Structural requirements for antimicrobial activity of p- coumaric acid derivatives
Summary,of Ph.D thesis
Development and evaluation of novel preservatives from simple organic acids xiv
LR mt-QSAR model for antimicrobial activity
pMICam = 0. 000312 W + 1.016 Eq. 2
n = 32 r = 0.823 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 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
Summary,of Ph.D thesis
Development and evaluation of novel preservatives from simple organic acids xv
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 p-
coumaric 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
Summary,of Ph.D thesis
Development and evaluation of novel preservatives from simple organic acids xvi
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 p-
amino 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 p-
coumaric 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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