Synthesis and biological evaluation of novel benzyl-substituted flavones as free radical (DPPH) scavengers and-glucosidase inhibitors

Article abstract of DOI:10.1080/10286020.2010.511190

Pharmacologically motivated natural product investigations have yielded a large variety of structurally unique lead compounds with interesting biomedical properties, but the natural roles of these molecules often remain unknown. In the present investigati

Full text of DOI:10.1080/10286020.2010.511190

Journal of Asian Natural Products Research
Vol. 12, No. 11, November 2010, 978–984
Synthesis and biological evaluation of novel benzyl-substituted flavones
as free radical (DPPH) scavengers and a-glucosidase inhibitors
G. Suresh Kumara, Ashok K. Tiwarib*, V. Rama Subba Raoa, K. Rajendra Prasada,
A. Zehra Alib and K. Suresh Babua*
aDivision of Organic Chemistry-I, Natural Product Laboratory, Indian Institute of Chemical
Technology, Tarnaka, Hyderabad 500 607, India; Division of Pharmacology, Indian Institute of
Chemical Technology, Tarnaka, Hyderabad 500 607, India
b
(Received 4 June 2010; final version received 23 July 2010)
Pharmacologically motivated natural product investigations have yielded a large
variety of structurally unique lead compounds with interesting biomedical properties,
but the natural roles of these molecules often remain unknown. In the present
investigation, a series of benzyl substituted-flavone derivatives have been synthesized
from the lead compounds and were screened against 1,1-diphenyl-2-picrylhydrazyl
(DPPH) free radical scavenging and a-glucosidase inhibitory properties. The resulting
activity profiles of these flavone derivatives were compared for degree of similarity to
the profile of 1–3. Most of the synthesized derivatives displayed potent activities when
compared to the parent compounds. Maximum potencies for DPPH free radical
scavenging activity were observed only in compounds containing the 4-hydroxyl
substitution and 3-methoxyl group on the phenyl ring. While the 2- and 4-hydroxyl
group substitutions on the phenyl ring seem to be crucial for the intestinal a-glucosidase
inhibitory activity.
Keywords: flavones; cinnamic acids; benzyl-substituted flavones; DPPH free radical
scavenging activity; a-glucosidase inhibitory activity
1. Introduction
because of their wide range of biological
activities such as antioxidant, antidiabetic,
anti-cancer, antibacterial, antiviral, anti-
inflammatory, antiallergic, and vasodila-
tory actions [3]. In addition, flavonoids
inhibit lipid peroxidation platelet aggrega-
tion, capillary permeability, and fragility,
and the activity of enzyme systems
including cyclooxygenase and lipoxygen-
ase [4]. Recent interest in these substances
has been stimulated by potential health
benefits arising from the antioxidant
activity and their high propensity to
transfer electrons, to chelate ferrous ions,
and to scavenge reactive oxygen species
[5]. Because of these properties, flavonoids
The search for novel therapeutic agents
and approaches for diabetes mellitus and
cardiovascular diseases is still an active
research field stimulated by the discovery
of new biological targets and by the
possibility of obtaining new bioactive
compounds with multiple biological
activities. The past decade has witnessed
an increasing interest in search of plant-
based lead compounds for the develop-
ment of new pharmaceuticals [1]. In this
regard, flavonoids/flavonoid derivatives,
which are the most common families of
green plant secondary metabolites [2],
have attracted the scientific interest
*Corresponding authors. Email: suresh@iict.res.in; tiwari@iict.res.in
ISSN 1028-6020 print/ISSN 1477-2213 online
q 2010 Taylor & Francis
DOI: 10.1080/10286020.2010.511190
http://www.informaworld.com

Journal of Asian Natural Products Research
979
have been considered as potential thera-
peutics of interest in combating multiple
disorders.
an optimal candidate among currently
available compounds for in vitro studies.
Herein, we report simple and new
synthetic methodology for the one-pot
synthesis of benzyl-substituted flavone
derivatives and their results of in vitro
free radical 1,1-diphenyl-2-picrylhydrazyl
(DPPH) and a-glucosidase inhibitory
potentials. This is the first report of the
synthesis of benzyl-substituted flavones.
For the synthesis of the target com-
pounds, we have developed new synthetic
strategy as depicted in Scheme 1. In our
initial experimentation for the synthesis of
compound 7, we used La(NO3)3·6H2O as
the catalyst with baicalein 1 and caffeic
acid 2; however, compound 7 was afforded
in 40% yield. In order to improve the
yields and synthesize flavone derivatives
expeditiously in the one-pot procedure, we
examined various Lewis acid catalysts
(Table 1). Among these, the best result was
obtained with CeCl3·7H2O–NaI (10
mol%) (Table 1, entry 2). We also tested
the effect of solvents on the formation of 7
and found that among MeOH, EtOH, 1,4-
dioxane, acetonitrile, dichloromethane,
dichloroethane, and THF, acetonitrile
was the best solvent in terms of the yield
and the reaction time (Table 2). Consider-
ing the amount of the catalyst, the reaction
time, the nature of the solvent, and the
yield, CeCl3·7H2O–NaI (10 mol%) [9] in
the acetonitrile system was found to be
effective, and subsequently this was
utilized for the preparation of a series of
derivatives. The reactions were completed
within 9–12 h. The products were formed
at reflux temperature and in high yields.
2. Results and discussion
In the course of our continuing efforts in
discovery and identification of potential
bioactive constituents from traditional
Indian flora, we have explored the use
of in vitro screening, in conjunction with
a pattern-matching algorithm, as a means
of identifying natural product extracts
potentially containing new free radical
scavenging and intestinal a-glucosidase
inhibitory leads [6]. Stemming from that
effort, we had reported the identification of
baicalein (1), oroxylin A (2), and chrysin
(3) (Figure 1) as bioactive principles
from the plant Oroxylum indicum [7] and
further demonstrated antibacterial effects
of oroxylin A (2) derivatives. We have
also reported antibacterial and a-glucosi-
dase inhibitory properties for the deriva-
tives of compounds 2 and 3 [7,8].
Prompted by the above-mentioned
biological properties of flavone derivatives
and in continuation of our previous work
on related analogs, the present study was
devised to synthesize new derivatives
using the above-mentioned lead com-
pounds and investigated their free radical
scavenging and a-glucosidase inhibitory
properties. We have also extended our
efforts to establish structure–activity
relationships within this biologically inter-
esting class of compounds, both to
ascertain potential directions for synthetic
lead optimization studies, and to identify
HO
O
O
HO
O
O
HO
HO
O
O
MeO
OH
OH
OH
Baicalein (1)
Oroxylin A (2)
Chrysin (3)
Figure 1. Structures of the lead compounds isolated from O. indicum.

980
G. Suresh Kumar et al.
R2
R3
OH
R2
O
HO
R1
O
O
H3C
HO
R1
OH
CeCl3 (5 mol%)
O
O
+
HO
Acetonitrile,
reflux conditions
OH
R1
OH
4. R1 = OH, R2 = H
5. R1 = OMe, R2 = H
6. R1 = H, R2 = OH
1. R1 = OH
2. R1 = OMe
3. R1 = H
7.R1 = R2 = OH, R3 = H
8. R1 = OH, R2 = OMe, R3 = H
9. R1 = OH, R2 = H,R3 = OH
10. R1 = OMe, R2 = OH, R3 = H
11. R1 = OMe, R2 = OMe,R3 = H
12. R1 = OMe, R2 = H, R3 = OH
13.R1 = H, R2 = OH, R3 = H
14. R1 = H, R2 = OMe, R3 = H
15. R1 = R2 = H, R3 = OH
Scheme 1. Synthesis of benzyl-substituted flavone derivatives.
Table 1. Studies on the catalyst optimization.
S. no.
Catalyst
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
10
La (NO3)3·6H2O (5 mol%)
CeCl3·7H2O NaI (10 mol%)
BF3.OEt2 (catalytic amount)
Bi (NO3)3·5H2O (5 mol%)
La (OTf)3 (5 mol%)
Cu (OTf)2 (5 mol%)
I2 (10 mol%)
InCl3 (10 mol%)
KHSO4·SiO2
Amberlyst-15 (10 mg)
15
12
20
20
15
18
18
20
24
15
40
80
Trace
Trace
40
30
50
20
None
75
The resulting crude compounds were
purified by column chromatography to
yield title compounds as racemic mixtures.
The biological significance of the
synthesized compounds was evaluated
in vitro for their potential for DPPH free
radical scavenging and rat intestinal a-
glucosidase inhibitory activity by methods
reported earlier [7]. Interestingly, DPPH
free radical scavenging activity was dra-
matically improved by the presence of the
benzyl ring on the flavone skeleton. The
activities were expressed in IC50 (concen-
tration required for 50% inhibition) values
(Table 3). As shown in Table 3, compounds
8, 10, and 14 showed potent DPPH free
radical scavenging activity and compounds
12 and 15 showed moderate a-glucosidase
inhibitory activity. Regarding the general
structure–activity relationship of com-
pounds, the following points were note-
worthy: (a) 3-hydroxy and 4-methoxy
substitution pattern in the phenyl ring, as
Table 2. Optimization of solvents.
S. no.
Solvent
Yield (%)a
1
2
3
4
5
6
7
8
9
Dichloroethane
THF
Ethanol
Acetonitrile
1,4-Dioxane
DMSO
Trace
Trace
60
80
45
None
None
20
ACOH
Acetonitrile þ water
Dichloromethane
Trace
Note: aIsolated yields.

Journal of Asian Natural Products Research
981
Table 3. DPPH scavenging and a-glucosidase inhibitory activities of benzyl-substituted flavone
derivatives.
DPPH scavenging activity
(SC50; mM)
a-Glucosidase inhibitory activity
(IC50; mM)
Compound
Baicalein
Oroxylin A
Chrysin
7
8
9
10
11
12
13
14
15
Trolox
Acarbose
34.48
NA
NA
25.78
43.45
67.74
NA
NA
NA
NA
NA
39.21
NA
13.47
8.05
47.85
7.54
12.13
46.19
17.88
6.93
58.05
5.96
–
512.58
44.11
–
18.63
Notes: NA ¼ not active (compounds were considered not active at a concentration of 50 mg/ml giving activity
less than 15%); IC50 or SC50 values were determined by linear regression analysis using at least five different
concentrations in triplicate and represent the mean of the experiment; SDM were within 10% in any case.
in compound 14, presents a better situation
to achieve a high degree of DPPH free-
radical scavenging activity. (b) With intact
of substitutions of 3-hydroxy and 4-
methoxy on the phenyl ring, introduction
of 6-hydroxyl or 6-methoxyl substitutions
of the flavone ring (8 and 11) led to the
decrease in the activity. However, neither
14 nor 8, 11 displayed a-glucosidase
inhibitory activity. (c) Comparing the
compounds 8, 11, and 14 with 7, 10, and
13, it was observed that 3- and 4-hydroxyl
group substitutions had less activity except
in 10, as showing more potent activity than
compound 11, respectively. However,
we were unable to obtain improvement in
a-glucosidase inhibitory activity. (d) Com-
parison of DPPH free radical scavenging
activity of 9, 12, and 15 with 7, 10, and
13 showed that the ortho positions of the
hydroxyl groups on the phenyl ring are
favorable for the activity compared to
the meta positions (as in compounds 9, 12,
and 15). It is important to mention that
all the synthesized derivatives exhibited
more potent activity than the flavones
(1–3), from which the derivatives have
been synthesized. This is the first report
identifying the DPPH free radical scaven-
ging and rat intestinal a-glucosidase
inhibitory activity for the benzyl-substi-
tuted flavones. All the new compounds
were characterized by detailed spectro-
scopic analysis [10].
In conclusion, we have developed the
synthetic methodology for the preparation
of flavonoid derivatives, and their DPPH
free radical scavenging and intestinal
a-glucosidase inhibitory properties were
investigated. The results of our study
indicated that 14, 10, and 8 showed potent
DPPH free radical scavenging activity,
while compound 15 displayed moderate
a-glucosidase inhibitory activity.
3. Experimental
3.1 General experimental procedures
Melting points were recorded on a Fisher
Johns apparatus and are uncorrected. FAB-
MS was recorded on a VG Auto spec-M
instrument. IR spectra were recorded on a
1
Nicolet spectrometer. H and 13C NMR
spectra were obtained on Varian 200,
400 MHz, and Bruker 300 MHz spec-
trometers using TMS as the internal

982
G. Suresh Kumar et al.
standard. HMBC, HSQC, and NOESY
experiments were obtained using an
Oxford 500 MHz spectrometer. The sol-
vents used were all of AR grade and were
distilled under the positive pressure of dry
nitrogen atmosphere where necessary.
Thin layer chromatography (TLC) was
performed on Merck silica gel 60 F254
plates. Visualization was performed using
5% H2SO4 solution followed by heating.
Column chromatography was performed
on silica gel (60–120 mesh) purchased
from Merck Specialities Private Ltd, Navi
Mumbai, India.
(3H, m), 7.31 (1H, s, OH), 6.77 (1H, br s),
6.72 (2H, br s), 6.54 (1H, s, H-3), 4.85 (1H,
q, J ¼ 7.2 Hz), 1.71 (3H, d, J ¼ 7.2 Hz).
13C NMR (75 MHz, CDCl3 þ DMSO-d6):
d (in ppm) 182.3, 163.2, 150.8, 147.9,
144.6, 143.8, 142.2, 136.0, 131.3, 130.7,
128.3 (2C), 127.8, 125.8 (2C), 117.4,
114.3, 113.9, 111.1, 104.5, 104.1, 32.0,
17.6. ESI-MS: m/z 407.1 [M þ H]þ.
3.3.2 Compound 8
IR nmax (KBr): 3450, 2924, 2853, 1651,
1030cm21 1H NMR (300MHz, CDCl3
.
þ DMSO-d6): d (in ppm) 12.81 (1H, s, OH),
8.80(1H, s, OH), 8.28(1H, s, OH), 7.56(2H,
m), 7.42 (3H, m), 6.97 (1H, s, OH), 6.83
(1H, s), 6.80 (1H, d, J ¼ 8.1 Hz), 6.73 (1H,
d, J ¼ 8.1 Hz), 6.55 (1H, s, H-3), 4.90 (1H,
q, J ¼ 7.1 Hz), 3.72 (3H, s, OMe), 1.75 (3H,
d, J ¼ 7.1 Hz).13C NMR (75 MHz, CDCl3
þ DMSO-d6): d (in ppm) 182.3, 163.2,
150.8, 147.9, 146.3, 144.7, 143.6, 135.9,
131.4, 130.7, 128.3 (2C), 127.9, 125.8 (2C),
119.0, 114.0, 110.7, 110.0, 104.5, 104.4,
55.2, 30.2, 17.9. ESI-MS: m/z 421.1
[M þ H]þ.
3.2 Extraction and isolation
Fresh O. indicum roots were collected
from the Manuguru forest, Andhra Pradesh
and processed as per the literature method
to obtain oroxylin A, baicalein, and
chrysin [10].
3.3 Typical experimental procedure for
the synthesis of benzyl flavones
A mixture of flavone (1 mmol), cinnamic
acid (2 mmol), and CeCl3·7H2O–NaI
(75 mg, 10 mol%) in acetonitrile/ethanol
was stirred at reflux temperature overnight.
After completion of the reaction (moni-
tored by TLC), the solvent was evaporated
to dryness and 50ml ice water was added.
The mixture was extracted with ethyl
acetate (3 £ 20ml), and the extracts were
washed with water (3 £ 20ml), dried over
Na2SO4, and the solvent was removed
using a rotary evaporator. The crude
mixture was chromatographed on silica
gel (100–200 mesh) to yield the target
compounds as racemic mixtures.
3.3.3 Compound 9
1H NMR (300 MHz, CDCl3 þ DMSO-d6):
d (in ppm) 12.83 (1H, s, OH), 9.12 (1H, s,
OH), 8.96 (1H, s, OH), 8.88 (1H, s, OH),
8.69 (1H, s, OH), 7.93 (2H, m), 7.52 (3H,
m), 7.08 (1H, d, J ¼ 8.4 Hz), 6.66 (1H, s,
H-3), 6.31 (1H, br s), 6.13 (1H, dd, J ¼ 8.4
and 1.7 Hz), 5.03 (1H, q, J ¼ 7.1 Hz), 1.67
(3H, d, J ¼ 7.1 Hz). 13C NMR (300 MHz,
CDCl3 þ DMSO-d6): d (in ppm) 182.5,
163.2, 157.2, 155.8, 155.2, 150.0, 131.0,
128.6 (2C), 128.2, 126.9, 126.2 (2C),
121.1, 110.9, 107.7, 106.1, 105.3, 104.1,
102.6, 102.2, 29.2, 18.0. ESI-MS: m/z
407.3 [M þ H]þ.
3.3.1 Compound 7
IR nmax (KBr): 3417, 2923, 2854, 1656,
1029 cm21 1H NMR (300 MHz, CDCl3
.
3.3.4 Compound 10
þ DMSO-d6): d (in ppm) 12.84 (1H, s,
OH), 8.72 (1H, s, OH), 8.24 (1H, s, OH),
7.82 (1H, s, OH), 7.57 (2H, m), 7.43
IR nmax (KBr): 3444, 2931, 2858, 1655,
1073 cm21 1H NMR (300 MHz, CDCl3
.

Journal of Asian Natural Products Research
983
þ DMSO-d6): d (in ppm) 12.99 (1H, s,
OH), 8.44 (1H, s, OH), 7.62 (1H, s, OH),
7.56 (2H, d, J ¼ 7.7 Hz), 7.43 (3H, m),
7.26 (1H, s, OH), 6.79 (1H, br s), 6.71
(2H, m), 6.54 (1H, s, H-3), 4.83 (1H, q,
J ¼ 7.2 Hz), 3.98 (3H, s, OMe), 1.71 (3H,
d, J ¼ 7.2 Hz). 13C NMR (75 MHz, CDCl3
þ DMSO-d6): d (in ppm) 182.4, 163.3,
153.8, 150.2, 150.0, 143.8, 142.1, 135.9,
131.0, 130.8, 130.2, 128.3 (2C), 125.8
(2C), 117.5, 114.3, 113.7, 110.9, 104.7,
104.4, 59.9, 31.9, 17.5. ESI-MS: m/z 421
[M þ H]þ.
106.09, 102.64, 102.16, 59.81, 30.31,
18.15. ESI-MS: m/z 421 [M þ H]þ.
3.3.7 Compound 13
IR nmax (KBr): 3357, 2923, 2853, 1653,
1028 cm21.1H NMR (300 MHz, CDCl3
þ DMSO-d6): d (in ppm) 12.73 (1H, s,
OH), 9.95 (1H, s, OH), 7.88 (2H, m), 7.73
(1H, s, OH), 7.53 (2H, m), 7.43 (1H, m),
7.25 (1H, s, OH), 6.78 (1H, br s), 6.72
(2H, m), 6.53 (1H, s, H-3), 6.36 (1H, s),
4.81 (1H, q, J ¼ 7.2 Hz), 1.68 (3H, d,
J ¼ 7.2 Hz). 13C NMR (75 MHz, CDCl3
þ DMSO-d6): d (in ppm) 181.8, 161.6,
143.7, 142.0, 136.1 131.1, 130.8, 130.6,
128.2 (2C), 125.7 (2C), 125.5, 117.7,
117.4, 114.1, 113.7, 104.9, 104.6, 98.9,
93.5, 29.0, 17.3. ESI-MS: m/z 391
[M þ H]þ.
3.3.5 Compound 11
IR nmax (KBr): 3438, 2936, 2851, 1656,
1072 cm21 1H NMR (300 MHz, CDCl3
.
þ DMSO-d6): d (in ppm) 12.98 (1H, s,
OH), 9.35 (1H, s, OH), 7.56 (2H, m), 7.51
(1H, s, OH), 7.43 (3H, m), 6.84 (1H, d,
J ¼ 1.3 Hz), 6.75 (1H, dd, J ¼ 8.1,1.3 Hz),
6.70 (1H, d, J ¼ 8.1 Hz), 6.55 (1H, s, H-3),
4.85 (1H, q, J ¼ 7.3 Hz), 4.09 (3H, s,
OMe), 3.75 (3H, s, OMe), 1.76 (3H, d,
J ¼ 7.3 Hz).13C NMR (75 MHz, CDCl3
þ DMSO-d6): d (in ppm) 182.3, 163.1,
154.3, 150.4, 150.2, 146.5, 143.9, 135.5,
131.2, 130.8, 130.5, 128.3 (2C), 125.8
(2C), 119.0, 114.3, 110.8, 110.3, 104.5
(2C), 59.8, 55.2, 32.3, 17.9. ESI-MS: m/z
435 [M þ H]þ.
3.3.8 Compound 14
IR nmax (KBr): 3312, 2922, 2852, 1647,
1032 cm21.1H NMR (300 MHz, CDCl3
þ DMSO-d6): d (in ppm) 13.27 (1H, s,
OH), 7.86 (2H, m), 7.62 (1H, s, OH), 7.50
(3H, m), 7.47 (1H, s, OH), 6.99 (1H, d,
J ¼ 8.1 Hz), 6.90 (1H, d, J ¼ 8.1, 1.7 Hz),
6.80 (1H, d, J ¼ 1.7 Hz), 6.66 (1H, s, H-3),
6.38 (1H, s), 4.86 (1H, q, J ¼ 7.3 Hz), 3.84
(3H, s, OMe), 1.64 (3H, d, J ¼ 7.3 Hz).
13C NMR (75 MHz, CDCl3 þ DMSO-d6):
d (in ppm) 182.5, 163.7, 161.5, 159.2,
156.2, 145.0, 134.4, 131.7, 129.1 (2C),
126.4, 126.3 (2C), 118.9, 116.0, 114.7,
114.2, 110.3, 109.7, 105.6, 95.3, 55.8,
31.8, 17.2. ESI-MS: m/z 405 [M þ H]þ.
3.3.6 Compound 12
IR nmax (KBr): 3376, 2922, 2850, 1656,
1046 cm21.1H NMR (300 MHz, CDCl3
þ DMSO-d6): d (in ppm) 13.0 (1H, s,
OH), 9.50 (1H, s, OH), 9.04 (1H, s, OH),
7.94 (2H, m), 7.51 (3H, m), 7.08 (1H, d,
J ¼ 8.1 Hz), 6.65 (1H, s, H-3), 6.34 (1H, s,
OH), 6.30 (1H, d, J ¼ 2.2 Hz), 6.25 (1H,
dd, J ¼ 8.1, 2.2 Hz), 5.03 (1H, q,
J ¼ 7.2 Hz), 3.85 (3H, s, OMe), 1.67
(3H, d, J ¼ 7.2 Hz).13C NMR (75 MHz,
CDCl3 þ DMSO-d6): d (in ppm) 182.5,
163.2, 157.3, 156.1, 155.1, 154.7, 150.0,
131.1, 129.0, 128.6 (2C), 126.9, 126.2
(2C), 121.11, 118.44, 117.57, 107.75,
3.3.9 Compound 15
IR nmax (KBr): 3440, 2923, 2853, 1653,
1037 cm21.1H NMR (300 MHz, CDCl3
þ DMSO-d6): d (in ppm) 12.85 (1H, s,
OH), 9.02 (1H, s, OH), 8.86 (1H, s, OH),
8.76 (1H, s, OH), 7.93 (2H, m), 7.50 (3H,
m), 6.84 (1H, d, J ¼ 8.4 Hz), 6.61 (1H, s,
H-3), 6.30 (1H, d, J ¼ 2.2 Hz), 6.25 (1H,
s), 6.22 (1H, dd, J ¼ 8.4, 2.2 Hz), 4.98

984
G. Suresh Kumar et al.
[3] L.H. Cazarolli, L. Zanatta, E.H. Alberton,
M.S.R.B. Figueiredo, P. Folador, R.G.
Damazio, M.G. Pizzolatti, and F.R.M.B.
Silva, Mini Rev. Med. Chem. 8, 1429
(2008).
(1H, q, J ¼ 7.2 Hz), 1.66 (3H, d,
J ¼ 7.2 Hz).13C NMR (75 MHz, CDCl3
þ DMSO-d6): d (in ppm) 182.0, 163.1,
159.0, 157.2, 155.7, 155.1, 154.5, 128.4
(2C), 126.9, 126.2 (2C), 118.4, 117.5,
107.7, 106.0, 105.2, 104.5, 102.6, 102.1,
99.2, 29.1, 17.7. ESI-MS: m/z 390
[M þ H]þ.
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Biochem. 7, 66 (1996).
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(2007).
3.4 Assay of a-glucosidase inhibitory
activity and DPPH free radical
scavenging activity
Determination of a-glucosidase inhibitory
activity and DPPH free radical scavenging
activity was done according to the
procedure described in the literature [7].
[7] T.H. Babu, V.R.S. Rao, A.K. Tiwari, K.S.
Babu, A.Z. Ali, and J.M. Rao, Bioorg.
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Acknowledgements
The authors thank Dr J.S. Yadav, Director,
IICT, for his encouragement and support during
the course of this work. G.S.K. and R.S.R.
thank CSIR, New Delhi for the financial
support.
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