Synthesis, characterization and molecular docking studies of novel 2-amino 3-cyano pyrano[2,3H]chrysin derivatives as potential antimicrobial agents

Article abstract of DOI:10.1007/s00044-015-1396-7

A series of novel 2-amino 3-cyano 4-aryl pyrano[2,3H]chrysin derivatives (3a-m) were efficiently synthesized by one-pot three-component reaction of aromatic aldehydes, malononitrile and chrysin and characterized by ¹H NMR, ¹³C NMR and mass spectral data. All the newly synthesized compounds were evaluated for their in vitro antimicrobial activity (antibacterial and antifungal). Among the tested compounds, 3a, 3g, 3h, 3j and 3k showed potent antibacterial activity compared to ciprofloxacin and the compounds 3a, 3g, 3h, 3i and 3k showed excellent antifungal activity compared to itrazole. The compounds 3a, 3g, 3h and 3k exhibited potent antimicrobial activity against all the selected pathogenic bacteria and fungi and emerged as potential molecules for further development. In addition, molecular modeling studies also performed to delineate the putative binding mode of these compounds. All of these chrysin derivatives (3a-m) obeyed the Lipinski's "rule of five" and have drug-likeness. Docking scores with appreciable binding energy values also exactly correlated with the experimental antimicrobial activity. The chemscore estimated by GOLD software was found to have a good correlation with the experimental inhibitory activity. Graphical Abstract: Docking of compound 3g with protein[Figure not available: see fulltext.] A series of novel 2-amino 3-cyano pyrano[2,3H]chrysin derivatives (3a-m) has been synthesized and evaluated for their antimicrobial activity along with molecular modeling studies[Figure not available: see fulltext.]

Full text of DOI:10.1007/s00044-015-1396-7

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MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-015-1396-7
ORIGINAL RESEARCH
Synthesis, characterization and molecular docking studies of novel
2-amino 3-cyano pyrano[2,3H]chrysin derivatives as potential
antimicrobial agents
P. Ramesh1,4 Ch. Sanjeeva Reddy2 K. Suresh Babu3 P. Muralidhar Reddy4
•
•
•
•
V. Srinivasa Rao5 T. Parthasarathy5
•
Received: 6 September 2014 / Accepted: 27 June 2015
Ó Springer Science+Business Media New York 2015
Abstract A series of novel 2-amino 3-cyano 4-aryl
pyrano[2,3H]chrysin derivatives (3a–m) were efficiently
synthesized by one-pot three-component reaction of
aromatic aldehydes, malononitrile and chrysin and
selected pathogenic bacteria and fungi and emerged as
potential molecules for further development. In addition,
molecular modeling studies also performed to delineate
the putative binding mode of these compounds. All of
these chrysin derivatives (3a–m) obeyed the Lipinski’s
‘‘rule of five’’ and have drug-likeness. Docking scores
with appreciable binding energy values also exactly
correlated with the experimental antimicrobial activity.
The chemscore estimated by GOLD software was found
to have a good correlation with the experimental inhi-
bitory activity.
1
characterized by H NMR, 13C NMR and mass spectral
data. All the newly synthesized compounds were eval-
uated for their in vitro antimicrobial activity (antibac-
terial and antifungal). Among the tested compounds, 3a,
3g, 3h, 3j and 3k showed potent antibacterial activity
compared to ciprofloxacin and the compounds 3a, 3g,
3h, 3i and 3k showed excellent antifungal activity
compared to itrazole. The compounds 3a, 3g, 3h and 3k
exhibited potent antimicrobial activity against all the
Graphical Abstract Docking of compound 3g with
protein
2
Department of Chemistry, Kakatiya University,
Warangal 506 009, India
& Ch. Sanjeeva Reddy
chsrkuc@yahoo.co.in
3
Division of Natural Product Chemistry, CSIR-Indian Institute
of Chemical Technology, Hyderabad 500 007, India
& K. Suresh Babu
suresh@iict.res.in
4
Department of Chemistry, Nizams PG College, Osmania
University, Hyderabad 500 007, India
& P. Muralidhar Reddy
pmdreddy@gmail.com
5
Department of Chemistry, Osmania University,
Hyderabad 500 007, India
1
Department of Chemistry, SR and BGNR Government
College, Khammam 507 002, India
123

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Med Chem Res
A series of novel 2-amino 3-cyano pyrano[2,3H]chrysin
derivatives (3a–m) has been synthesized and evaluated for
their antimicrobial activity along with molecular modeling
studies
including anticancer, anti-inflammatory, antioxidant and
antiallergic activities (Habtemariam, 1997; Fishkin and
Winslow, 1997; Pearce et al., 1984; Wolfman et al., 1994;
Kubo et al., 2000; Liu et al., 1992). In the previous studies,
few chrysin derivatives and their biological activities have
been reported by the modification at C-7 of A-ring (Suresh
babu et al., 2006; Peng Cheng et al., 2010; Xiao et al.,
2011).
In the light of the wide range of biological activities
associated with the pyran and fused 4H-pyran derivatives
(Khafagy et al., 2002; Ferrerira et al., 2010; Vyas et al.,
2009; Martnez et al., 1997), we focused on the synthesis of
novel pyrano[2,3H]chrysin derivatives via multi-compo-
nent reactions (MCRs) and investigation of their in vitro
antimicrobial activities. Herein, we report the synthesis and
in vitro antimicrobial activities of a series of novel 2-amino
3-cyano 4-aryl pyrano[2,3H]chrysin derivatives along with
their molecular modeling studies. To the best of our
knowledge, this is the first report on the synthesis of
chrysin derivatives containing pyran ring.
Keywords Chrysin Á Pyrano[2,3H]chrysin Á
Multi-component reaction Á Antimicrobial activity Á
Molecular docking studies
Results and discussion
Chemistry
Introduction
The search for novel therapeutic agents and approaches for
antimicrobial agents is still an active research field stimu-
lated by the discovery of new biological targets and by the
possibility of obtaining new bioactive compounds with
multiple biological activities. The past decade has wit-
nessed an increasing interest in search of plant-based lead
compounds for the development of new pharmaceuticals
(Newman et al., 2003). In this regard, flavonoids and fla-
vonoid derivatives, which are the most common families of
green plant secondary metabolites (Bohm, 1998; Harborne
and Baxter, 1999; Havsteen, 2002; Skibola and Smith,
2000), have attracted the scientific interest because of their
wide range of biological activities such as antioxidant,
antidiabetic, anticancer, antibacterial, antiviral, anti-in-
flammatory, antiallergic and vasodilatory actions (Cazarolli
et al., 2008). In addition, flavonoids inhibit lipid peroxi-
dation (LPO) platelet aggregation, capillary permeability,
fragility and activity of enzyme systems including
cyclooxygenase and lipoxygenase (Cook and Samman,
1996). Recent interest in these substances has been stim-
ulated by the 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 (Van Acker et al., 1996). As part of our
program on the synthesis of heterocyclic derivatives and
screening of their biological activities, we have been
attracted toward the chrysin, a natural flavone which has
been reported to exhibit numerous biological activities
In our attempts to develop a facile one-pot three-compo-
nent protocol to synthesize target molecules, initially we
focused on the efficient synthesis of chrysin by following
the literature procedure (Scheme 1; Ranga Rao et al., 2009;
Anuradha et al., 2006; Nishino et al., 2003; Messanga
et al., 1992). As shown in Scheme 2, chrysin was treated
with aromatic aldehydes and malononitrile in presence of
catalytic amount of piperidine in ethanol to yield the novel
pyrano[2,3H]chrysin derivatives (3a–m) in good yields
within the 4–9 h of reaction times. The structures of all the
newly synthesized compounds were well characterized by
1H NMR, 13C NMR and mass data. 1H NMR spectra of the
compounds (3a–m) showed the formation of pyran ring
with a singlet peak between 4.56 and 5.27 ppm corre-
sponding to Ar–CH proton of pyran ring and another sin-
glet peak for 2H of –NH2 group between 5.69 and
7.33 ppm. 13C NMR spectra also confirm the formation of
pyran ring with a signal between 33.26 and 35.77 ppm
corresponding to Ar–CH carbon of pyran ring. ESI–MS
spectra showed characteristic molecular ion [M ? H]?
peaks corresponding to the molecular weight of synthe-
sized compounds. It is important to mention that the
electron-donating groups and the electron-withdrawing
groups on the aromatic ring had some impact on the
reaction rates as well as the yields of the products. As
indicated in Table 1, aryl aldehydes containing electron-
withdrawing groups took less time to complete the reaction
123

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Med Chem Res
HO
O
O
HO
Ph-CHO
a)
OH
HO
OH
O
b)
OH
OH
O
OH
1
2
Reagents:
a). KOH, Ethanol, rt, 6h.
b). I2 , Trigol, 120oC, 2h
Scheme 1 Synthesis of chrysin (2)
R
CN
H
NH2
CHO
O
OH
+
O
O
O
Piperidine / Ethanol
Reflux, 6-10 hrs
+
CH2(CN)2
R
O
OH
OH
3a-m
2
3a: R = H
3h: R = 4-CH3
3i: R = 4-OH
3b: R = 2-Cl
3c: R = 4-Cl
3d: R = 4-Br
3e: R = 3-NO2
3f: R = 4-NO2
3g: R = 3-F, 4-CH3
3j: R = 4-OCH3
3k: R = 4-N(CH3)2
3l: R = 3-OH 4-OCH3
3m: R = 3-OC2H5, 4-OH
Scheme 2 Syntheses of novel 2-amino 3-cyano pyrano[2,3H]chrysin analogues (3a–m)
Table 1 One-pot synthesis of different novel 2-amino 3-cyano 4-aryl pyrano[2,3H]chrysin derivatives catalyzed by piperidinea
Entry
Product
R
Time (h)
Yieldsb (%)
M.P (°C)
1
3a
3b
3c
3d
3e
3f
R=H
7
6
5
5
4
6
7
7
8
8
9
9
9
78
84
89
88
95
92
74
68
66
72
62
58
60
289–290
298–299
300–301
305–306
296–297
278–279
274–275
286–287
298–299
284–285
260–261
280–281
264–265
2
R=2-Cl
3
R=4-Cl
4
R=4-Br
5
R=3-NO2
6
R=4-NO2
7
3g
3h
3i
R=3-F-4-CH3
R=4-CH3
8
9
R=4-OH
10
11
12
13
a
3j
R=4-OCH3
R=4-N(CH3)2
R=3-OH-4-OCH3
R=3-OC2H5-4-OH
3k
3l
3m
All the reactions were performed with substituted aromatic aldehyde (1.2 equiv), malononitrile (1.2 equiv) and chrysin (1.0 equiv) catalyzed
by piperidine (10 mol%)
b
Yields refer to isolated products (based on chrysin)
123

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Med Chem Res
Scheme 3 Plausible
Piperidine / Ethanol
Ar-CHO + CH2(CN)2
Ar-CH=C(CN)2
arylidine malononitrile
mechanism for the formation of
pyrano[2,3H]chrysin derivatives
(3a–m)
knoev nagel
e
condensation
(step-1)
O
O
O-
O
OH
Ar
HC
C
Piperidine (B)
-BH+
OH
O
OH
C
C
Chrysin
N
N
Michael-type
addition
(step-2)
CN
CN
Ar
H
NH2
Ar
C
O
O
Cyclization
(step-3)
H
NH
O
O
O
OH
O
OH
Pyrano[2,3H]chrysin derivatives
and provided higher yields than their electron-donating
counterparts.
antibacterial and antifungal activity. Ciprofloxacin and
itrazole were used as reference drugs for antibacterial and
antifungal activity, respectively. The results were recorded
for each tested compound as the average diameter for
inhibition zones of bacterial or fungal growth round the
disk in millimeter. The minimum inhibitory concentration
(MIC) measurement determined for compounds showed
significant growth inhibition zones using twofold serial
dilution method (Shamroukh et al., 2007; Keche et al.,
2013). The inhibition zone diameter values and MIC (lg/
mL) values are presented in Table 2. The results revealed
that most of the tested compounds displayed variable
inhibitory effects on the growth of the tested Gram-positive
and Gram-negative bacterial strains and also against fungal
strains.
The plausible mechanism for the formation of com-
pounds (3a–m) is shown in Scheme 3 which involved three
steps. The initial step is assumed to be the Knoevenagel
condensation between the aromatic aldehyde and
malononitrile to form arylidinemalononitrile intermediate
in situ. In the next step, the intermediate undergoes
Michael-type addition with chrysin at eighth position fol-
lowed by an intramolecular cyclization to give 2-amino
3-cyano pyrano[2,3H]chrysin derivative.
Biology
Antimicrobial evaluation
The compounds 3a, 3g and 3j showed excellent
antibacterial activity with inhibitory zone [20 mm. The
compounds 3h, 3i and 3k showed significant activity. The
compounds 3b, 3c, 3d, 3e and 3f showed moderate activity;
3l and 3m showed least activity with respect to the refer-
ence drug ciprofloxacin (Fig. 1). The MIC values of
compounds 3a, 3g, 3h, 3i, 3j and 3k also support the
inhibitory activity. The compounds 3a, 3g, 3h, 3i and 3k
showed excellent antifungal activity with inhibitory zone
[20 mm; the compounds 3f and 3j also showed good
antifungal activity. The other compounds 3b, 3c, 3d, 3e, 3l
and 3m showed moderate activity (Fig. 2). The MIC values
also support the findings.
In order to search for the potent antimicrobial agent from
these newly synthesized compounds (3a–m), they were
evaluated for their in vitro antibacterial activity against
Pseudomonas aeruginosa (ATCC 27853) and Escherichia
coli (ATCC 25922) as examples of Gram-negative bacte-
ria, and Bacillus licheniformis (ATCC 14580) and Sta-
phylococcus aureus (ATCC 25923) as examples of Gram-
positive bacteria. These compounds were also evaluated for
their in vitro antifungal activity against Candida albicans
(ATCC 76615) and Fusarium oxysporum (ATCC 16417).
Agar-diffusion method (Sridhar et al., 2004; Patel et al.,
2012) was used for the determination of the preliminary
123