In Vitro antioxidant, antimicrobial and admet study of novel furan/benzofuran C-2 coupled quinoline hybrids

Article abstract of DOI:10.22159/ijpps.2017v9i11.21413

Objective: Synthesis of novel 2-(benzofuran-2-yl) and 2-(furan-2-yl) quinoline-4-carboxylates and their [2-(1-benzofuran-2-yl) quinolin-4-yl] methanol, [2-(1-furan-2-yl) quinolin-4-yl] methanol and its derivatives for antioxidant, antimicrobial and in silico pharmacokinetic study. Methods: Synthesis was carried with the conventional method and the structures were confirmed by IR, 1H NMR, 13C NMR and mass spectral analysis. The antioxidant activity was performed by DPPH and H2O2 radical scavenging method. The antimicrobial investigation was established by cup plate and food poison technique. The in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) study of the drug was carried out in ACD/lab-2. Results: The antioxidant activity results revealed that compounds 4b-c, 5a-b, 10c and 10f exhibited good DPPH radical and hydrogen peroxide scavenging activity. The antibacterial results revealed that compounds 4c, 5a-b, 10b, 10d and 10f exhibited good activity against Escherichia coli, Klebsiella pneumonia and Salmonella typhimurium. Further, the antifungal activity results showed that compounds 4c, 5c and 10c-e were showing good activity against Aspergillusflavus and Candida neoformans. The mean value of P<0.05 were considered to be statistically significant. The ADMET results revealed that compounds emerged as a potential candidate for antioxidant and antimicrobial agents. Conclusion: The study reveals that compounds containing furan/benzofuran coupled heterocycles played the important role for activity as they possess potent antioxidant and antimicrobial agents. The in silico ADME analysis also suggesting the compounds were in acceptable range to obey the pharmacokinetic parameters.

Full text of DOI:10.22159/ijpps.2017v9i11.21413

International Journal of Pharmacy and Pharmaceutical Sciences
ISSN- 0975-1491
Vol 9, Issue 11, 2017
Original Article
IN VITRO ANTIOXIDANT, ANTIMICROBIAL AND ADMET STUDY OF NOVEL
FURAN/BENZOFURAN C-2 COUPLED QUINOLINE HYBRIDS
ANANTACHARYA RAJPUROHIT1, NAYAK D. SATYANARAYAN*1, SAMEER PATIL2, KITTAPPA M. MAHADEVAN3,
ADARSHA H. J.4
1Department of Pharmaceutical Chemistry, Kuvempu University, Post Graduate Centre,Kadur577548, Chikkmagluru Dt., Karnataka St. India,
2Department of Post Graduate Studies and Research in Biochemistry, JnanaSahyadri, Kuvempu University,Shankaraghatta577451,
Shivamogga Dt., Karnataka State, India, 3Department of Chemistry, Kuvempu University, Post Graduate Centre,Kadur577548, Chikkmagluru
Dt., Karnataka St. India, 4Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560 012 India
Email: satya1782005@gmail.com
Received: 17 Jul 2017 Revised and Accepted: 21 Sep 2017
ABSTRACT
Objective: Synthesis of novel 2-(benzofuran-2-yl) and 2-(furan-2-yl) quinoline-4-carboxylates and their [2-(1-benzofuran-2-yl) quinolin-4-yl]
methanol, [2-(1-furan-2-yl) quinolin-4-yl] methanol and its derivatives for antioxidant, antimicrobial and in silico pharmacokinetic study.
Methods: Synthesis was carried with the conventional method and the structures were confirmed by IR, 1H NMR, 13C NMR and mass spectral
analysis. The antioxidant activity was performed by DPPH and H2O2 radical scavenging method. The antimicrobial investigation was established by
cup plate and food poison technique. The in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) study of the drug was
carried out in ACD/lab-2.
Results: The antioxidant activity results revealed that compounds 4b-c, 5a-b, 10c and 10f exhibited good DPPH radical and hydrogen peroxide
scavenging activity. The antibacterial results revealed that compounds 4c, 5a-b, 10b, 10d and 10f exhibited good activity against Escherichia coli,
Klebsiella pneumonia and Salmonella typhimurium. Further, the antifungal activity results showed that compounds 4c, 5c and 10c-e were showing
good activity against Aspergillusflavus and Candida neoformans. The mean value of P<0.05 were considered to be statistically significant. The ADMET
results revealed that compounds emerged as a potential candidate for antioxidant and antimicrobial agents.
Conclusion: The study reveals that compounds containing furan/benzofuran coupled heterocycles played the important role for activity as they
possess potent antioxidant and antimicrobial agents. The in silico ADME analysis also suggesting the compounds were in acceptable range to obey
the pharmacokinetic parameters.
Keywords: DPPH, Lipinski, ADMET, Toxicity, Escherichia coli and Aspergillusflavus
© 2017 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
DOI: http://dx.doi.org/10.22159/ijpps.2017v9i11.21413
(phenylamino) furo-[2, 3-b] quinoline and 2-(furan-2-yl)-4-
(phenylamino) quinoline derivatives for cytotoxicity evaluation and
1-{4-[(furo[2, 3-b] quinoline-4-yl) amino] phenyl} ethanone
exhibited potent and broad spectrum of cytotoxicity [23, 24]. The
quinoline ring system is an essential structural fragment of a large
number of natural and synthesized compounds displaying
interesting biological activities such as antimalarial, antibacterial,
anti-asthmatic, antihypertensive, and anti-inflammatory [25-27].
Quinolines and their derivatives have been found applications as
pharmaceuticals and agrochemicals, as well as being general
INTRODUCTION
Free radicals are species capable of free existence that contains one
or more unpaired electrons which react with another molecule by
accepting or donating the electrons [1]. The harmful intervention of
reactive oxygen species (ROS) in normal metabolic processes leads
to pathologic changes which is a consequence of their interaction
with biomolecules inside and outside the cells [2, 3]. ROS contain
molecules like hydrogen peroxide (H2O2); hydroxyl radical (·OH) and
superoxide (Oz-), by the generation of ROS, there is an alteration in
the normal functioning of the cell and leads to pathophysiological
changes. Free radicals are responsible for causing a wide number of
health hazards such as cancer, ageing, heart diseases and gastric
problems, etc. Oxygen free radicals disintegrate DNA and destroy
cell membranes by enzymatic metabolic processes [4-6]. In nature’s
collection of biologically active molecules, benzofuran derivatives
constitute a major group [7-9]. Benzofuran ring systems bearing
substitutions at the C-2 position are widely distributed in nature and
have been reported to have antioxidant, antiviral, antifungal
activities [10, 11], antimicrobial [12, 13], anti-inflammatory [14],
antipsychotic [15], analgesic [16], antilipidemic [17] and CNS
stimulant activities [18]. Investigation of benzofuran derivatives in
search of new drugs or to increase the efficacy of the present drugs
has been most frequent approach [19]. Similarly, furan and its
analogues were found to be biologically useful. 2-(furan-2-yl)
quinoline-4-carboxylic acid and its analogues were reported to have
the inhibiting property of C. albicans prolyl-tRNA synthetase and
showed potent in vitro antifungal activities against dermatophytes
[20, 21], 2-(furan-2-yl)-4-(phenoxy) quinoline derivatives were
screened for cytotoxicity and anti-inflammatory activities [22], 4-
synthetic building blocks [28-31]. Molecular hybridization is
a
rational approach to design new prototypes after coupling different
pharmacophoric subunits that can be recognized by two or more
biologic receptors [32]. These strategies have been used in drug
discovery to increase the efficacy.
In view of these observations and in continuation of our work on
drug discovery through cinchophene and their derivatives [33-36],
herein we report a facile, inexpensive procedure in the preparation
of novel hybrid molecules [2-(1-benzofuran-2-yl) quinolin-4-yl]
methanol and [2-(1-furan-2-yl) quinolin-4-yl] methanol derivatives
using mild conditions, and explored for their in vitro antioxidant,
antimicrobial and preliminary in silico ADMET properties.
MATERIALSANDMETHODS
Materials
Chemicals used in the synthesis of compounds were from Alfa Aesar,
Pvt. Ltd. Bangalore, India and Spectrochem Pvt. Ltd. Bangalore,
India. The solvents were of reagent grade and when necessary, they

Satyanarayan et al.
Int J Pharm Pharm Sci, Vol 9, Issue 11, 144-153
were purified and dried. Melting points of the synthesized
compounds were determined with the help of Raga digital melting
point apparatus and are uncorrected; Infrared data were recorded
on a Bruker spectrophotometer using KBr pellets. 1H and 13C NMR
spectra were recorded on Bruker AVANCE II 400 and 100 MHz
instruments using DMSO-d6/CDCl3 as a solvent and TMS as an
internal standard; chemical shifts are expressed as δ values (ppm).
The J values are expressed in Hertz (Hz). Mass spectra (MS) were
recordedin JEOL GCMATE II LC–Mass spectrometer with electron
mixture was cooled to room temperature and poured onto the
crushed ice. The resulting solid mass was filtered, washed with
water, dried and recrystallized from petroleum ether (60-80).
General procedure for the synthesis of substituted [2-(1-furan-
2-yl) quinolin-4-yl] methanol 10(a-f)
The synthesis of substituted [2-(1-furan-2-yl) quinolin-4-yl]
methanol 10(a-f) is similarly to the synthesis of analogues 5(a-c).
Spectral details
impact ionization (EI)
technique. Analytical thin-layer
chromatography (TLC) was performed with precoated TLC sheets of
silica gel 60 F254 (Merck, Darmstadt, Germany), visualized by long
and short wavelength UV lamps (nm). Chromatographic
purifications were performed on Merck silica gel (100-200 mesh).
[2-(1-benzofuran-2-yl) quinolin-4-yl] methanol (5a)
Yield: 78 %. M. Pt. 154-156 °C; IR (KBr)νmax3114 (-O-H stretching),
3062, 1665, 1595, 1253 cm-1; 1H NMR (DMSO-d6, 400 MHz, δ ppm):
8.20 (1H, d, J=8 Hz, H-13), 8.10 (1H, s, H-19), 7.87 (1H, d, J=12 Hz, H-
16), 7.58 (4H, m, H-9, 8, 7, 15), 7.50 (1H, t, J=8 Hz, H-6), 7.353 (1H, t,
J=1.2 Hz, H-14), 7.260 (1H, t, J=2.4 Hz, H-3), 5.25 (2H, s, H-20), 1.72
(1H, s, quinolin-4-yl] methanol–OH proton); 13C NMR (DMSO-d6, 100
MHz, δ ppm): 159.1 (C, C-18), 157.1 (C, C-2), 156.6 (C, C-10), 154.5
(C, C-5), 154.0 (CH, C-13), 145.8 (CH, C-14), 141.2 (C, C-12), 139.6 (C,
C-15), 123.6 (CH, C-16), 123.2 (CH, C-8), 122.6 (CH, C-9), 122.1 (CH,
C-7), 121.5 (C, C-4), 115.8 (C, C-17), 114.9 (CH, C-19), 113.9 (CH, C-
6), 108.5 (CH, C-3), 67.0 (CH2, C-20). Calcd. 275.3 gm/ml. EI-MS
(m/z): 276.0 (M+1).
Methods
Synthesis of 1-(1-benzofuran-2-yl) ethanone(1)
Synthesis of 1-(1-benzofuran-2-yl) ethanonewas achieved by the
addition of salicylaldehyde (5.8 g, 0.047 mol), chloroacetone (4.3g,
0.047 mol) to an alcoholic KOH (33 %, 20 ml) solution and kept for
stirring vigorously for about 2-3 h. maintaining a temperature 0-5
°C. The resultant mixture was poured onto crushed ice. The
separated solid was filtered and recrystallized from petroleum ether
(60-80). The yield was 85 %, M. Pt.75-78 °C.
[2-(1-benzofuran-2-yl)-6-chloroquinolin-4-yl] methanol (5b)
General procedure for the synthesis of substituted 2-(1-
benzofuran-2-yl) quinoline-4-carboxylic acid 3(a-c)
Yield: 81 %. M. Pt. 206-208 °C; IR (KBr), νmax3120 (-O-H stretching),
2920, 1605, 1260 cm-1; 1H NMR (DMSO-d6,400 MHz, δ ppm): 8.16
(1H, d, J=4 Hz, H-13), 8.14 (1H, s, H-19), 7.91(1H, d, J=4 Hz, H-8),
7.68 (1H, t, J=4 Hz, H-8), 7.66 (1H, d, J=4 Hz, H-14), 7.653 (1H, d,
J=0.4 Hz, H-7), 7.63 (1H, s, H-3), 7.37 (1H, t, J=4 Hz, H-9), 7.314 (1H,
d, J=0.8 Hz, H-6), 5.23 (2H, s, H-21), 1.55 (1H, s, quinolin-4-yl]
methanol–OH proton); 13C NMR (DMSO-d6,100 MHz, δ ppm):154.9
(C, C-18), 154.5 (C, C-5), 148.7 (C, C-2), 148.4 (C, C-10), 145.8 (C, C-
12), 131.4 (C, C-15), 131.2 (CH, C-14), 130.4 (CH, C-13), 128.6 (CH, C-
7), 125.9 (C, C-4), 125.7 (C, C-17), 123.5 (CH, C-16), 122.7 (CH, C-8),
122.1 (CH, C-19), 115.5 (CH, C-9), 111.5 (CH, C-6), 106.6 (CH, C-3),
59.7 (CH2, C-21). Calcd. 309.30gm/ml. EI-MS (m/z): 276.0 (M+1).
A mixture of 1-(1-benzofuran-2-yl) ethanone (1.8 g, 0.0113 mol) and
substituted 1H-indole-2, 3-dione (1.5 g, 0.0113 mol) in ethanol (10
ml) and anaqueous solution of KOH (33 %) 5 ml was added, the
reaction mixture was stirred at 65-70 οC for about12-14 h. The
reaction mixture was extracted with ethyl acetate (2-3 times) and
the aqueous layer was poured onto crushed ice, acidified with 10 M
HCl and the resulting mass was filtered and dried to get yellow
amorphous powder, yield 80 %.
General procedure for the synthesis of substituted methyl 2-(1-
benzofuran-2-yl) quinoline-4-carboxylates 4(a-c)
[2-(1-benzofuran-2-yl)-8-fluoroquinolin-4-yl] methanol (5c)
Analogues of 2-(1-benzofuran-2-yl) quinoline-4-carboxylic acids were
dissolved in sufficient quantity of methanol with a catalytic amount of
Conc. H2SO4 and the mixture were refluxed for about 10-12 h. The
reaction mixture was cooled to room temperature and poured onto
the crushed ice, filtered, washed with water, dried and recrystallized
from petroleum ether (60-80) and ethyl acetate (3:1v/v).
Yield: 79 %. M. Pt. 158-160 °C; IR (KBr)νmax 3114 (-O-H stretching),
3063, 1597, 1253 cm-1; 1H NMR (DMSO-d6, 400 MHz, δ ppm): 8.20
(1H, d, J=8 Hz, H-16), 8.12 (1H, s, H-19), 7.89 (1H, d, J=8 Hz, H-6),
7.62 (3H, m, H-15, 9, 7), 7.51 (1H, t, J=8 Hz, H-8), 7.35 (1H, t, J=8 Hz,
H-14), 7.26 (1H, t, J=8 Hz, H-3), 5.26 (2H, s, H-21), 1.65 (1H, s,
quinolin-4-yl] methanol-OH proton); 13C NMR (DMSO-d6,100 MHz, δ
ppm):154.9 (C, C-18), 154.8 (C, C-5), 149.1 (C, C-2), 148.0 (C, C-10),
147.2 (C, C-12), 129.9 (CH, C-15), 129.4 (CH, C-14), 128.3 (C, C-13),
126.6 (CH, C-7), 125.7 (C, C-4), 124.8 (C, C-17), 123.4 (CH, C-16),
122.0 (CH, C-8), 114.4 (CH, C-9), 111.5 (CH, C-6), 106.1 (CH, C-3),
59.6 (CH2, C-21). Calcd. 293.00 gm/ml.
General procedure for the synthesis of substituted [2-(1-
benzofuran-2-yl) quinolin-4-yl] methanol 5(a-c)
To a 100 ml round bottom flask, dissolve methyl 2-(1-benzofuran-2-
yl) quinoline-4-carboxylate in sufficient quantity of ethanol and
maintain the reaction mixture below 5 °C, followed by the addition
of sodium borotetrahydride until effervesces ceases. Stir the
reaction mixture overnight at room temperature and pour onto the
crushed ice after neutralizing with 10 M HCl. The solid mass
obtained was filtered, washed with water, dried and recrystallized
from ethyl alcohol.
[6-chloro-2-(furan-2-yl) quinolin-4-yl] methanol (10a)
Yield: 88 %. M. Pt. 148-150 °C; IR (KBr)νmax 3200 (-O-H stretching),
2918, 1672, 1604, 1249, 748 cm-1; 1H NMR (DMSO-d6, 400 MHz, δ
ppm): 8.05 (1H, d, J=1.2 Hz, H-9), 7.92 (1H, s, H-12), 7.86 (1H, s, H-
15), 7.631 (2H, t, J=0.8 Hz, H-4, 3), 7.221 (1H, d, J=7.2 Hz, H-5), 6.590
(1H, m, H-10), 5.16 (2H, s, H-17), 1.68 (1H, s, quinolin-4-yl]
methanol-OH proton); 13C NMR (DMSO-d6,100 MHz, δ ppm): 152.9
(C, C-14), 148.6 (C, C-2), 148.4 (C, C-6), 145.8 (C, C-8), 131.1 (CH, C-
5), 130.5 (C, C-11), 130.2 (CH, C-10), 125.3 (CH, C-9), 122.7 (C, C-13),
114.8 (CH, C-12), 112.6 (CH, C-15), 110.7 (CH, C-4), 59.7 (CH2, C-
17).Calcd. 259.68 gm/mol. EI-MS (m/z): 260.0 (M+1).
General procedure for the synthesis of substituted 2-(1-furan-2-
yl) quinoline-4-carboxylic acid 8(a-f)
The compounds 8 (a-f) was synthesized by literature method [37]
with slight modification. After completion of the reaction, the
reaction mixture was chilled in a nice bath. The solid mass of the
sodium salt of cinchonic acid was collected by filtration. The residue
was dissolved in water and acidified with 10 % glacial acetic acid,
filter the residue and repeatedly washed with ethyl acetate (4-5
times).
[6-bromo-2-(furan-2-yl) quinolin-4-yl] methanol (10b)
Yield: 83 %. M. Pt. 151-153 °C; IR (KBr)νmax 3215 (-O-H stretching),
2923, 1670, 1603, 1248 cm-1; 1H NMR (DMSO-d6, 400 MHz, δ ppm):
8.022 (1H, d, J=0.7 Hz, H-9), 7.98 (1H, d, J=8 Hz, H-15), 7.90 (1H, s, H-
12), 7.740 (1H, d, J=2.4 Hz, H-5), 7.630 (1H, d, J=1.2 Hz, H-10), 7.21
(1H, d, J=4 Hz, H-3), 6.58 (1H, m, H-4), 5.14 (2H, s, H-17), 1.67 (1H, s,
quinolin-4-yl] methanol-OH proton); 13C NMR (DMSO-d6, 100 MHz, δ
ppm): 152.9 (C, C-14), 148.6 (C, C-2), 148.2 (C, C-6), 145.9 (CH, C-5),
132.7 (CH, C-10), 131.2 (CH, C-9), 125.9 (CH, C-12), 125.8 (CH, C-11),
General procedure for the synthesis of substituted methyl2-(1-
furan-2-yl) quinolone-4-carboxylates 9(a-c)
Analogues of 2-(1-furan-2-yl) quinoline-4-carboxylic acids were
dissolved in sufficient quantities of methanol with a catalytic amount
of Conc. H2SO4 and was refluxed for about 12-14 h. The progress of
the reaction was tartan by TLC. After completion, the reaction
145

Satyanarayan et al.
Int J Pharm Pharm Sci, Vol 9, Issue 11, 144-153
119.1 (CH, C-15), 114.7 (C, C-13), 112.6 (CH, C-3), 110.8 (CH, C-4),
notations of the derivatives were then fed in the online free version
2011.06 to calculate various molecular properties and to predict the
bioactivity score for drug targets including enzymes and nuclear
receptors, kinase inhibitors, GPCR ligands and ion channel
modulators. Molecular properties such as partition coefficient (Log
P), topological polar surface area (TPSA), hydrogen bond donors and
acceptors, rotatable bonds, number of atoms, molecular weight, and
violations of Lipinski’s rule of five were calculated to evaluate the
drug-likeness of the synthesized compounds [40]. The bioactivity
score and drug-likeness properties of the title compounds were
compared with the standard drugs streptomycin, ciprofloxacin and
pyrazinamide respectively.
59.7 (CH2, C-17). Calcd. 304.13 gm/ml. EI-MS (m/z): 304.13 (M+).
[8-fluoro-2-(furan-2-yl) quinolin-4-yl] methanol (10c)
Yield: 82 %. M. Pt. 85-87 °C; IR (KBr)νmax 3112 (-O-H stretching), 2921,
1
1603, 1250 cm-1; H NMR (DMSO-d6,400 MHz, δ ppm): 7.89 (1H, s, H-
15), 7.60 (2H, t, J=4 Hz, H-11, 4), 7.36 (2H, d, J=4 Hz, H-10, 12), 6.58
(1H, d, J=4 Hz, H-3), 5.15 (2H, s, H-17), 1.66 (1H, s, quinolin-4-yl]
methanol-OH proton); 13C NMR (DMSO-d6, 100 MHz, δ ppm): 158.6 (C,
C-14), 156.1 (C, C-9), 153.0 (C, C-2), 149.0 (CH, C-5), 148.3 (C, C-8),
145.1 (CH, C-11), 137.3 (C, C-13), 126.1 (CH, C-12), 119.4 (CH, C-15),
114.5 (CH, C-10), 113.8 (C, C-6), 112.6 (CH, C-3), 110.9 (CH, C-4), 59.7
(CH2, C-17). Calcd. 243.23 gm/ml. EI-MS (m/z): 244.10 (M+1).
Biological evaluation
[6-chloro-2-(5-methylfuran-2-yl) quinolin-4-yl] methanol (10d)
DPPH free radical scavenging assay
Yield: 77 %. M. Pt. 136-138 °C; IR (KBr)νmax 3186 (-O-H stretching),
2897, 1672, 1607, 1245, 752 cm-1; 1H NMR (DMSO-d6, 400 MHz, δ
ppm): 8.03 (1H, d, J=8 Hz, H-10), 7.83 (2H, d, J=4 Hz, H-11, 13), 7.59
(1H, d, J=4 Hz, H-16), 7.12 (1H, d, J=4 Hz, H-3), 6.191 (1H, d, J=0.8 Hz,
H-4), 5.14 (2H, s, H-18), 2.46 (3H, s, H-6), 1.81 (1H, s, quinolin-4-yl]
methanol-OH proton); 13C NMR (DMSO-d6, 100 MHz, δ ppm): 154.4 (C,
C-15), 151.5 (C, C-7), 148.1 (C, C-5), 145.8 (C, C-2), 131.0 (C, C-9),
130.2 (C, C-12), 130.0 (CH, C-10), 125.1 (CH, C-11), 122.7 (C, C-14),
114.6 (CH, C-13), 112.1 (CH, C-16), 109.0 (CH, C-3, 4), 59.7 (CH2, C-18),
13.6 (CH3, C-6).Calcd. 273.71 gm/ml. EI-MS (m/z): 274.08 (M+1).
The assay was performed after modification of the method
described by Blois [41]. 0.1 ml of different concentrations of
amethanolic solution of standard and test compounds (0.5, 0.75, 1.0,
1.25 and 1.5 mg/ml) was added to 2 ml of DPPH methanolic solution
(60 mm). The mixture was shaken vigorously and allowed to react at
room temperature and in darkness for 5 h. The absorbance of the
resulting solution was measured at 517 nm using
a UV/Vis
spectrophotometer after 5 h incubation. Scavenging of DPPH free
radicals was calculated as:
DPPH scavenging activity (%) = [(Ac–At)/Ac] × 100
[6-bromo-2-(5-methylfuran-2-yl) quinolin-4-yl] methanol (10e)
Where Ac is the absorbance of the control tube (containing all
reagents except the test compound), and At is the absorbance of the
test tube. Ascorbic acid was used as the standard in the
concentration range of 0.5-1.5 mg/ml.
Yield: 81 %. M. Pt. 104-106 °C; IR (KBr)νmax 3206 (-O-H stretching),
2922, 1667, 1535, 1245 cm-1; 1H NMR (DMSO-d6, 400 MHz, δ ppm):
7.970 (1H, d, J=2 Hz, H-10), 7.93 (1H, d, J=8 Hz, H-11), 7.77 (1H, s, H-
13), 7.701 (1H, d, J=2 Hz, H-16), 7. 09 (1H, d, J=4 Hz, H-4), 6.181 (1H,
d, J=0.8 Hz, H-4), 5.09 (2H, s, H-18), 2.45 (3H, s, H-6), 1.93 (1H, s,
quinolin-4-yl] methanol-OH proton); 13C NMR (DMSO-d6, 100 MHz, δ
ppm): 154.4 (C, C-15), 151.4 (C, C-5), 148.6 (C, C-7), 147.9 (C, C-2),
146.0 (C, C-9), 132.6 (C, C-12), 131.1 (CH, C-11), 125.8 (CH, C-10),
125.6 (C, C-14), 118.8 (CH, C-13), 114.6 (CH, C-16), 112.1 (CH, C-4),
109.0 (CH, C-3), 59.7 (CH2, C-18), 13.5 (CH3, C-6). Calcd. 318.16
gm/ml. EI-MS (m/z): 318.04 (M+).
Hydrogen peroxide scavenging assay
H2O2 scavenging power was determined according to the method of
Ruch and co-workers [42]. The method is based on the ability of a
compound to convert hydrogen peroxide to water. 40 mm solution of
hydrogen peroxide was prepared in saline phosphate buffer (pH 7.4).
100 μl DMSO solutions of the test compounds or standards at the
concentrations of 0.5, 0.75, 1.0, 1.25 and 1.5 mg/ml were separately
added to 2 ml of the prepared hydrogen peroxide solution and the
absorbance was measured at 230 nm after 10 min against a blank
solution. The hydrogen peroxide scavenging activity for compounds
and standards was calculated using the following equation
[8-fluoro-2-(5-methylfuran-2-yl) quinolin-4-yl] methanol (10f)
Yield: 78 %. M. Pt. 118-120 °C; IR (KBr)νmax 3332 (-O-H stretching),
2922, 1599, 1247 cm-1; 1H NMR (DMSO-d6,400 MHz, δ ppm): 7.76
(1H, s, H-16), 7.52 (1H, t, J=4 Hz, H-12), 7.30 (2H, m, H-13, 3), 7.13
(1H, d, J=4 Hz, H-4), 6.16 (1H, d, J=4 Hz, H-11), 5.10 (2H, s, H-18),
2.42 (3H, s, H-6), 1.81 (1H, s, quinolin-4-yl] methanol-OH proton);
13C NMR (DMSO-d6,100 MHz, δ ppm): 158.6 (C, C-15), 154.4 (C, C-7),
151.5 (C, C-5), 148.7 (C, C-9), 148.3 (C, C-2), 125.9 (CH, C-12), 125.5
(C, C-10), 119.3 (CH, C-11), 114.9 (C, C-14), 113.9 (CH, C-13), 113.7
(CH, C-16), 112.2 (CH, C-4), 109.0 (CH, C-3), 59.7 (CH2, C-18), 13.6
(CH3, C-6). Calcd. 257.25 gm/ml. EI-MS (m/z): 358.00 (M+1).
H2O2 scavenging activity (%) = [(Ac-At)/Ac] × 100
Where Ac is the absorbance of the control and At is the absorbance
of the tested compounds or standards. Ascorbic acid at the
concentration range of 0.5-1.5 mg/ml was used as the standard.
Antibacterial activity
Cup plate method
Pharmacokinetic parameter studies
ADME-toxicity prediction
The antibacterial activity of synthesized molecules was studied
systematically against three different strains of bacteria such as E.
coli (ATCC No. 25922), K. pneumonia (ATCC No. 700603) and S.
typhimurium (ATCC No. 14028) (gram-negative) by the agar
diffusion method [43-45]. The organisms were subcultured using
nutrient agar medium. The tubes containing sterilized medium were
inoculated with respective bacterial strain. After incubation at 37±1
°C for 24 h. They were stored in a refrigerator. The flasks with
incubated bacterial inoculums were prepared by transferring a
loopful of stock culture to nutrient broth (100 ml) and incubated at
37±1 °C for 18 h. Before the experimentation, solutions of the test
compounds were prepared by dissolving 2 ml each in dimethyl
sulphoxide (5 ml). Reference standards for gram-negative bacteria
were made by dissolving accurately weighed the quantity of
Streptomycin respectively in dimethyl sulphoxide solution,
separately. The nutrient agar medium was sterilized by autoclave at
121 °C (15 lb/sq. inch).
The molecular descriptors of synthesized compounds (4a-c, 5a-c and
10a-f) are predicted by pharmacokinetics parameters like absorption,
distribution, metabolism, excretion and toxicity (ADMET). The
ADMET/SAR [38] helps to evaluate biologically active molecules and
eliminate a biologically poor molecule, an active lead molecule which
contains undesirable functional groups based on Lipinski rule. The
statistical calculation for lead molecules includes surface area,
geometry and fingerprint properties which help to understand
biological important endpoints. Aqueous solubility (PlogS), blood-
brain barrier penetration (QlogBB), intestinal absorption (logHIA)
[39] and hepatotoxicity, Caco-2 cell permeability (QPPCaco) also help
to predict the toxicity of lead molecules with intraperitoneal, oral,
intravenous and subcutaneous toxic effects. The in silico study enables
to decide the safety and efficacy of active molecules take up the
molecule for in-depth studies.
The petri-plates, test tubes and flasks containing medium is plugged
with cotton were sterilized in hot air-oven at 160 °C, for an hrs. Into
each sterilized pertained plate (10 cm diameter), about 20 ml each
of molten nutrient bacteria (6 ml of inoculums to 300 ml of nutrient
Calculation of pharmacokinetic parameters and toxicity potential
Chemical structures and SMILES notations of the title compounds
were obtained by using ACD labs Chem sketch version 12.0. SMILES
146

Satyanarayan et al.
Int J Pharm Pharm Sci, Vol 9, Issue 11, 144-153
agar medium) was transferred, aseptically. The plates were left at
room temperature to allow for solidification. On each plate, four
cups of 6 mm diameter were made with a sterile cork borer. Then,
0.1 ml of the test solution was added to the cups, aseptically and
labelled, accordingly. The plates were kept undisturbed for at least 2
h. at room temperature to allow diffusion of the solution properly,
into the nutrient agar medium. All the experiments were carried out
in triplicate. Simultaneously, controls were maintained employing
0.1 ml of dimethyl sulphoxide to observe the solvent effects. After
incubation of the plates at 37±1 °C for 24 h, the diameter of the zone
of inhibition was read with the help of antibiotic zone scale.
triplicate in order to minimize the errors. The inhibition percentage
of the A. flavusand C. neoformansmycelial growth was calculated
using the following formula.
IP = 100 x CT
Where C is the average of 3 replicates of mycelial growth (cm) of
control petri dishes and T is the average of 3 replicates of mycelial
growth (cm) of treated petri dishes. Fluconazole was used as the
positive control and DMSO was thus used as the negative control.
RESULTSANDDISCUSSION
Chemistry
Antifungal activity
Poisoned food technique was performed to investigate the
antifungal effect of test compounds against Aspergillusflavus and
Cryptococcus neoformans. Synthesized compounds were tested for
their antifungal activity [46]. The fungi employed for screening were
sub-cultured using potato dextrose agar medium. The potato-
dextrose-agar medium was sterilized by autoclave at 121 °C (15
lb/sq. inch), for 15 min. The petri-plates, tubes and flasks plugged
with cotton were sterilized in an autoclave at 121 °C, for an hour.
Into each sterilized petri-plate (10 cm diameter), about 30 ml each
of molten potato dextrose-agar medium inoculated with the
respective fungus (5 mm disc of the fungus grown) was transferred,
aseptically. The petri dishes were incubated at 28±1°C temperature.
The diameter of the zone of inhibition was read with the help of an
‘antibiotic zone reader’. The experiments were performed in
The synthesis of key intermediate 1-(1-benzofuran-2-yl) ethanone
(1) and its utilization in the construction of 2-(1-benzofuran-2-yl)
quinoline-4-carboxylic acids 3(a-c) and 8(a-f) are shown in Scheme-
I, II and table 1. The intermediate (1) was synthesized by stirring a
mixture of 2-hydroxybenzaldehyde with chloroacetone inbasic
medium using methanol as solvent. Subsequently, 2-(1-benzofuran-
2-yl) quinoline-4-carboxylic acids 3(a-c) were synthesized by the
reaction of a compound (1) with substituted isatins 2(a-c) in basic
medium to obtain the products 3(a-c). The ester, methyl 2-(1-
benzofuran-2-yl) quinoline-4-carboxylates 4(a-c) were synthesized by
reacting 3(a-c) with methyl alcohol in the presence of catalytic amount
of Conc. H2SO4 to obtain the product in good yield. The alcohol 5(a-c)
was synthesized by the reaction of compound 4(a-c) with reducing
agent sodium borotetrahydride, under stirring condition.
Table 1: Particulars of the derivatives of [2-(1-benzofuran-2-yl) quinolin-4-yl] methanol and [2-(1-furan-2-yl) quinolin-4-yl] methanol
S. No.
Samples code
R
Molecular formula
C19H13NO3
C19H12ClNO3
C19H12FNO3
C18H13NO2
Molecular weight
303.31
337.75
301.30
275.30
(%)yield
Melting point ( °C)
115-118
125-128
122-124
154-156
1
2
3
4
5
6
4a
4b
4c
5a
5b
5c
-H-
-Cl
-F
-H-
-Cl
-F
83
85
80
78
81
79
C18H12ClNO2
C18H12FNO2
309.00
293.00
206-208
158-160
R
-H-
-H
-H-
-CH3
-CH3
-CH3
R1
7
8
9
10
11
12
10a
10b
10c
10d
10e
10f
-Cl
-Br
-F
-Cl
-Br
-F
C14H10ClNO2
C14H10BrNO2
C14H10FNO2
C15H12ClNO2
C15H12BrNO2
C15H12FNO2
259.68
304.13
243.23
273.71
318.16
257.25
88
83
82
77
81
78
148-150
151-153
85-87
136-138
104-106
118-120
IR spectra of the compounds showed an absorption band in the
range of 3114 cm-1 due to the characteristic-OH group stretching.
4-yl] methanol, and the peaks between δ 159.1 to 108.5 ppm
corresponding to aromatic carbons. MS analysis of 5(a-c) displayed
their corresponding molecular ion peak confirming their molecular
weight. IR spectra of the compounds showed the absorption band at
3215 cm-1 characteristic of-OH is stretching for different alcohols.
The 1H NMR spectra of 10a showed a singlet at δ 5.16 ppm
corresponding to methyl protons of [quinolin-4-yl] methanol, and
another singlet at δ 1.68 ppm corresponding to the alcohol proton of
[quinolin-4-yl] methanol.
The 1H NMR spectra of 5a showed
a singlet at δ 5.25 ppm
corresponding to methyl protons of [quinolin-4-yl] methanol, shown
a singlet at δ 1.72 ppm corresponding to alcohol proton of methyl
alcohol and the remaining peaks which appeared at δ 8.20 to 7.26
ppm corresponding to aromatic protons of the quinoline and
benzofuran rings. The 13C-NMR spectra of 5a showed a characteristic
peak at δ 67.0 ppm corresponding to the methyl carbon of [quinolin-
O
OH
O
33 % KOH
EtOH
+
O
O
N
O
O
N
Reflux 12-14 hrs.
R
H
R
3(a-c)
(1)
2(a-c)
Reflux 10-12 hrs.
MeOH/H2SO4
O
O
OH
EtOH/NaBH4
R. T. Stirr.
12-14 hrs.
O
N
O
N
R
R
5(a-c)
4(a-c)
R-H-,-Cl and-F
Scheme I: Synthesis of substituted [2-(1-benzofuran-2-yl) quinolin-4-yl] methanol 5(a-c)
147

Satyanarayan et al.
Int J Pharm Pharm Sci, Vol 9, Issue 11, 144-153
O
OH
O
30 % NaOH
O
+
R
R
O
N
O
O
N
40-45 min.
H
R1
R1
8(a-f)
6(a-b)
7(a-c)
Reflux 12-14 hrs. MeOH/H2SO4
O
O
OH
EtOH/NaBH4
R
O
N
R
R. T. Stirr.
12-14 hrs.
O
N
R1
R1
10(a-f)
9(a-f)
R
R1
-Cl
-Br
-F
-H-
-H-
-H-
-CH3
-CH3
-CH3
-Cl
-Br
-F
Scheme II: Synthesis of substituted [2-(1-furan-2-yl) quinolin-4-yl] methanol 10(a-f)
The peaks between δ 8.08 to 6.59 ppm corresponding to benzofuran
and quinoline ring protons. The 13C-NMR spectra of 10a showed a
peak at δ 59.7 ppm corresponding to the methyl carbon of [quinolin-
4-yl] methanol, and the peaks between δ 152.9 to 110.7 ppm
corresponding to aromatic carbons. MS analysis of 10a displayed the
molecular ion peak confirming their molecular weight. The 1H NMR
spectra of 10d showed a singlet at δ 5.14 ppm corresponding to
methyl protons of [quinolin-4-yl] methanol, it showed singlet at δ
2.46 ppm corresponding to furan substituted methyl protons and
appeared a singlet at δ 1.81 ppm corresponding to the alcohol
proton of [quinolin-4-yl] methanol and the aromatic peaks which
appeared between δ 8.05 to 6.19 ppm. The 13C-NMR spectra of 10d
showed a peak at δ 59.7 ppm corresponding to the methyl carbon of
[quinolin-4-yl] methanol, peak at δ 13.6 ppm corresponding to the
methyl carbon of furan substituted methyl and the peaks between δ
154.4 to 109.0 ppm corresponding to aromatic carbons.
good, acceptable range and hence, further used to make an oral
formulation for absorption and to transport proteins and metabolizing
enzymes to maintain homeostatic condition. The intestinal absorption
(logHIA) and Caco-2 cell permeability (PCaco-2) within the range of-2
poor absorption and+2 more absorption reveal that the compounds are
more permeable in the intestine and helps for good transport of the drug
or its metabolites.
The reference range of-5 (poor) to+1 (good) and substrate inhibitor
from 0 to 1 in which the reference and test compounds 4a-c, 5a-c
and 10a-f shows significant activity with human intestinal
absorption and metabolism. The aqueous solubility of compounds
lies with a range of 0 (poor) to 2 (good) showed that all the
molecules have good solubility. While the reference compound, as
well as test compounds, came within the acceptable range (table 3).
The toxicity of the substituted [2-(1-benzofuran-2-yl) quinolin-4-yl]
methanol and [2-(1-furan-2-yl) quinolin-4-yl] methanol was
predicted. The probability of health effects was predicted using
ACD/I-Lab 2.0 (guest). The toxicity of selected compounds was listed
in table 2. The LD50 of potential compounds detects the cumulative
potential of acute toxicity that is administered through oral,
subcutaneous, intra peritoneal, intravenous and subcutaneous on
mouse models. The comparative analysis of reference compounds
with test compounds on subcutaneous, intra-peritoneal, oral and
intravenous is low when compared to the reference molecule. The
toxicity results suggest that the compounds 4a-c, 5a-c and 10a-f have
less toxic effect to tissue and with no side effect (table 2). Hence, can
be considered for further development.
In silico ADMET (Absorption, distribution, metabolism,
excretion and toxicity) profile
The compounds with poor bioavailability show less effectiveness against
disease. To overcome this problem, predicting bioavailability properties
will be of great advantage in drug development. Hence, using computer-
based methods like ADMET and SAR tools the molecular descriptors and
drug likeliness properties was studied. The pharmacokinetic properties
are represented in table 2 and 3. The in silico data of all the molecules
displayed are within acceptable range. The interpretation of test
compounds with reference standards (streptomycin, fluconazole and
ascorbic acid) show that the compounds 4a-c, 5a-c and 10a-f were in
Table 2: LD50 ADME-TOX parameters and probability of health effects of substituted [2-(1-benzofuran-2-yl) quinolin-4-yl] methanol and
[2-(1-furan-2-yl) quinolin-4-yl] methanol using ACD/I-Lab 2.0
Ligands
Intraperitoneala
490(0.45)
500(0.4)
Oralb
Intravenousc
55(0.49)
56(0.48)
58(0.47)
46(0.47)
42(0.47)
47(0.47)
65(0.4)
67(0.35)
78(0.38)
62(0.39)
59(0.35)
67(0.38)
110(0.67)
580(0.47)
820(0.58)
Subcutaneousd
490(0.28)
550(0.33)
940(0.34)
620(0.25)
520(0.28)
570(0.29)
470(0.38)
770(0.33)
760(0.33)
500(0.39)
720(0.34)
680(0.32)
400(0.52)
2700(0.23)
2700(0.5)
4a
540(0.15)
450(0.18)
460 (0.15)
840 (0.32)
810 (0.28)
690 (0.32)
800 (0.25)
870 (0.34)
550 (0.29)
780 (0.23)
840 (0.34)
580 (0.34)
880(0.53)
1000(0.51)
4500(0.61)
4b
4c
640(0.46)
420(0.34)
400(0.34)
620(0.44)
260(0.43)
280(0.36)
380(0.28)
260(0.44)
250(0.37)
350(0.29)
310(0.76)
1200(0.73)
1100(0.7)
5a
5b
5c
10a
10b
10c
10d
10e
10f
Streptomycin
Fluconazole
Ascorbic acid
Estimated LD50-mouse value in mg/kg after Intraperitoneala, Oralb, Intravenousc and Subcutaneousd administration, The drugs with amoderate
effect on reliability index (>0.5), The drugs with borderline effect on reliability index (>0.3,<0.5).
148

Satyanarayan et al.
Int J Pharm Pharm Sci, Vol 9, Issue 11, 144-153
Table 3: ADME and pharmacological parameters prediction for the ligands substituted [2-(1-benzofuran-2-yl) quinolin-4-yl] methanol
and [2-(furan-2-yl) quinolin-4-yl] methanol using ADMET/SAR
Ligands
4a
4b
4c
5a
5b
5c
10a
10b
10c
10d
10e
PlogBBa
0.9430
0.9656
0.9709
0.9866
0.9906
0.9931
0.9906
0.9892
0.9931
0.9876
0.9855
0.9907
0.9712
0.9382
0.8532
PCacob
0.5416
0.5853
0.5732
0.5175
0.5510
0.5465
0.5510
0.5277
0.5464
0.5621
0.5388
0.5559
0.8824
0.9894
0.7710
logHIAc
1.0000
1.0000
1.0000
1.0000
1.0000
1.0000
1.0000
1.0000
1.0000
1.0000
1.0000
1.0000
0.6968
0.8867
0.6559
logpGI (Non-substrate)d
0.7113
0.7231
0.7055
0.7710
0.7642
0.7690
0.7642
0.7637
0.7690
0.7598
0.7568
0.7609
0.5531
0.6008
0.8696
logpGI (Non-inhibitor)e
0.9010
0.8397
0.7329
0.7075
0.8692
0.8247
0.8692
0.8377
0.8247
0.8859
0.8570
0.8566
0.7577
0.8782
0.9347
PlogSf
logpappg
1.0868
1.1113
1.1292
1.2208
1.2692
1.2863
1.2692
1.2573
1.2863
1.2395
1.2205
1.2440
-0.5128
1.3598
-0.3148
-3.4558
-4.3351
-3.9795
-2.8564
-3.8706
-3.4170
-3.8706
-3.6714
-3.4170
-3.7943
-3.6238
-3.3745
-2.0122
-1.8626
0.1081
10f
Streptomycin
Fluconazole
Ascorbic acid
aPredicted blood/brain barrier partion coefficient (1-high penetration, 2-medium penetration and 3-low penetration). bpredicted Caco-2 cell
c
permeability in nm/s (acceptable range-1 is poor,+1 is great). predicted human intestinal absorption in nm/s (acceptable range 0 is poor,>1 is
great). dpredicted P-glycoprotein Substrate in nm/s (acceptable range of-5 is poor, 1 is great). epredicted P-glycoprotein inhibitor in nm/s
f
(acceptable range 0-1). predicted aqueous solubility, (Concern value is 0-2 highly soluble). gpredicted Caco-2 cell Permeability in cm/s (Concern
value is-1 to 1).
non-violation of Lipinski’s rule of five, suggesting poor membrane
permeability across the cell. Partition coefficient values of
streptomycin, ciprofloxacin and pyrazinamide, the standard drugs
were found to be well under 5 justifying their oral use. Molecular
weight of twelve furan quinoline derivatives was found to be less
than 500 and thus, molecules are likely to be easily transported,
diffused and absorbed as compared to large molecules. A number
of hydrogen bond acceptors (O and N atoms) and number of
hydrogen bond donors (NH and OH) in the synthesized
compounds 4a-c, 5a-c and 10a-fwere in accordance with the
Lipinski’s rule of five i.e. less than 10 and 5, respectively. It can be
predicted that the synthesized derivatives were likely to be orally
active as they obeyed Lipinski’s rule of five. The topological polar
surface area is very much concurrently with the hydrogen bonding
of a molecule and is a very good indicator bioavailability of drug
molecules. TPSA of synthesized derivatives were observed in the
range of 46.26-52.34 A ° and are well below the limit of 160 A °.
Drug-likeness score of the entitled compounds
Lipinski’s rule of five is generally used by pharmaceutical chemists
in drug design and development to predict bioavailability of lead
or drug molecules. According to Lipinski’s rule of five, a candidate
molecule will likely be orally active, if: i) the calculated
octanol/water partition coefficient (Log P)<5, ii) the molecular
weight is under 500, iii) there were less than 5 hydrogen bond
donors (OH and NH groups) and, iv) there are less than ten
hydrogen bond acceptors (notably
N and O). The molecular
properties of [2-(1-benzofuran-2-yl) quinolin-4-yl] methanol and
[2-(1-furan-2-yl) quinolin-4-yl] methanol derivatives (4a-c, 5a-c
and 10a-f) were calculated and are represented in table 4.
Compounds (4a, 4c, 5a-c and 10a-f) did not violate any of the
Lipinski’s rules of five and were expected to be orally active.
Molecular hydrophobicity indicated by Log P values for all the title
compounds except 4b was found to be equal to 5 and it is in clear,
Table 4: Drug likeness score for the synthesized [2-(1-benzofuran-2-yl) quinolin-4-yl] methanol and [2-(1-furan-2-yl) quinolin-4-yl]
methanol derivatives (4a-c, 5a-c and 10a-f)
Compounds
4a
4b
4c
5a
5b
5c
10a
10b
10c
10d
10e
miLog Pa
4.34
5.00
4.46
3.85
4.50
3.97
3.20
3.33
2.66
3.42
3.55
2.88
-1.40
-4.87
-0.12
TPSAb
52.34
52.34
52.34
46.26
46.26
46.26
46.26
46.26
46.26
46.26
46.26
46.26
107.22
324.42
81.6
n-Atoms
23
24
24
21
22
22
18
18
18
19
19
19
12
40
22
n-ONc
n-OHNHd
n-Violation
n-rotbe
MWf
4
4
4
3
3
3
3
3
3
3
3
3
6
18
7
0
0
0
1
1
1
1
1
1
1
1
1
4
15
1
0
0
0
0
0
0
0
0
0
0
0
0
0
3
0
3
3
3
2
2
2
2
2
2
2
2
2
2
9
5
303.32
337.76
321.34
275.31
309.75
293.30
259.69
304.14
243.24
273.72
318.17
257.26
176.12
580.59
306.28
10f
Ascorbic acid
Streptomycin
Fluconazole
Antioxidant studies
DPPH radical scavenging assay
The antioxidant potential of synthesized compounds (4a-c, 5a-c and 10a-
f) was determined as an index of pharmacological usefulness. Two in
vitro models were used to evaluate antioxidant properties; radical
scavenging and hydrogen peroxide scavenging activity. The antioxidant
properties were expressed in terms of percentage inhibition and 50
percent inhibitory concentration (IC50) values (table 5and6).
The antioxidant potential of compounds (4a-c, 5a-c and 10a-f)
was determined by in vitro model systems(Blois 1958) and were
used for the evaluation of antioxidant properties, namely, 2, 2-
diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity
and expressed in terms of 50% inhibitory concentration (IC50
values (table 6).
)
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Int J Pharm Pharm Sci, Vol 9, Issue 11, 144-153
Table 5: Antioxidant activity of substituted [2-(1-benzofuran-2-yl) quinolin-4-yl] methanol and [2-(1-furan-2-yl) quinolin-4-yl] methanol
derivatives (4a-c, 5a-c and 10a-f)
Compounds code
DPPH scavenging activity % inhibition
H2O2 scavenging activity % inhibition
4a
4b
4c
5a
68±0.57
71±1.0
82±1.52
65±1.52
74±1.0
64±1.0
70±0.57
68±0.57
69±1.0
5b
70±2.5
5c
10a
10b
10c
10d
10e
10f
63±1.72
56±1.52
46±1.0
85±1.52
57±1.0
61±1.15
79±1.52
96±1.15
58±1.0
52±3.02
45±1.52
72±1.72
52±0.57
64±1.52
69±2.64
76±1.0
Ascorbic acid
Values are expressed as mean±SD (n=3). Values are significant with each other at P<0.05 (Duncan’s multiple range test).
The DPPH radical scavenging assay is one of the best free radicals
scavenging mechanism (Scheme-III) by which antioxidant inhibits
the oxidation and offer a rapid technique for screening the radical
scavenging activity of specific compounds. All tested molecules
Hydrogen peroxide (H2O2) scavenging capacity assay
The hydrogen peroxide scavenging ability of synthesized
derivatives was determined according to the method of Ruch and
co-workers 1989 [42].
exhibited
a certain degree of radical scavenging activity. The
compounds 4c, 5b, 10c and 10f exhibited good radical scavenging
potential (table 5) compared with standard, ascorbic acid.
A solution of H2O2 (40 mm) was prepared in phosphate buffer
(pH 7.4).
O
O
N
OH
O
N
O
N
R
N
R
+
O
N
O
N
O N
-H.
O
O
O
O
N
O
O
N
R
O
O
N
O
+
NH
O
N
N
Scheme III: The mechanism for the reaction of compounds 5a-c with DPPH radical
Table 6: IC50 (µg/ml) values of DPPH and H2O2 scavenging activity of substituted [2-(1-benzofuran-2-yl) quinolin-4-yl] methanol and [2-(1-
furan-2-yl) quinolin-4-yl] methanol analogues (4a-c, 5a-c and 10a-f)
Compounds code
DPPH scavenging activity IC50 (µg/ml)
H2O2 scavenging activity IC50(µg/ml)
4a
4b
4c
5a
5b
5c
10a
10b
10c
10d
10e
10f
16.8±0.57
17.4±0.25
20±1.0
16±1.52
15.5±0.20
16±1.15
15±1.0
14.5±0.23
9.8±0.11
11±0.20
8.2±1.15
18±1.0
11.5±0.20
15±1.52
13.2±0.30
7.5±0.20
16.5±0.2
18±1.15
16.5±0.2
11.5±0.23
9.5±0.20
24±0.57
12±1.52
16±1.15
13.8±0.15
6±1.52
Ascorbic acid
Values are expressed as mean±SD (n=3). Values are significant with each other at P<0.05 (Duncan’s multiple range test).
150

Satyanarayan et al.
Int J Pharm Pharm Sci, Vol 9, Issue 11, 144-153
The solutions of different molecules (10-50 μg/ml) were prepared in
phosphate buffer and were added to H2O2 solution (0.6 ml, 40 mm).
The absorbance value of the reaction mixture was recorded at 230 nm.
The blank solution contains phosphate buffer without H2O2.The
percentage of an H2O2 scavenging of the entitled molecule and the
standard compound was calculated as H2O2 radical scavenging activity.
The compounds 4b, 5a, 10c and 10f exhibited good radical
scavenging potential when compared with standard, ascorbic acid.
Antibacterial activity
The in vitro antibacterial activity of entitled compounds was
determined by the agar well diffusion method. In this study, E. coli,
K. pneumonia and S. typhirium (Gram-negative) were selected
because of its infectious nature. The test compounds were dissolved
in dimethyl sulfoxide (DMSO) at concentrations of 5 and 10 μg/ml
(table 7).
(%) = [{Ao-A1/Ao}] ×100
WhereAo is the absorbance of H2O2, A1 is the absorbance of H2O2
solution in the presence of benzofuran/furan quinolone methanols.
Table 7: Antimicrobial activities of substituted [2-(1-benzofuran-2-yl) quinolin-4-yl] methanol and [2-(1-furan-2-yl) quinolin-4-yl]
methanol analogues (4a-c, 5a-c and 10a-f)
Samples code
E. coli
K. pneumonia
5 µg/ml
3.2±0.08
2.8±0.12
2.7±0.17
3.2±0.12
2.8±0.09
3.1±0.12
3.0±0.12
2.8±0.15
3.1±0.12
3.4±0.21
3.2±0.20
3.0±0.12
3.4±0.21
S. typhimurium
5 µg/ml
2.5±0.11
2.3±0.12
3.4±0.12
3.0±0.09
3.1±0.2
3.3±0.17
2.8±0.10
3.1±0.12
3.0±0.12
2.7±0.12
3.4±0.22
2.5±0.22
3±0.12
5 µg/ml
2.4±0.14
2.6±0.17
3.1±0.12
3.4±0.17
3.3±0.17
2.4±0.25
2.6±0.17
3.4±0.17
2.4±0.27
3.2±0.26
2.7±0.31
2.8±0.12
2.7±0.12
10 µg/ml
2.9±0.11
3.1±0.17
3.5±0.21
3.9±0.12
3.6±0.18
3.0±0.18
3.4±0.26
3.6±0.12
2.8±0.18
3.5±0.09
3.1±0.12
3.4±0.12
3.8±0.09
10 µg/ml
3.4±0.14
3.4±0.17
3.6±0.26
3.6±0.26
3.5±0.22
3.4±0.08
3.5±0.12
3.2±0.12
3.3±0.18
3.8±0.35
3.6±0.12
3.6±0.25
3.6±0.26
10 µg/ml
3.0±0.11
3.0±0.17
3.6±0.31
3.4±0.20
3.6±0.12
3.8±0.35
3.3±0.17
3.4±0.21
3.5±0.17
2.9±0.12
3.8±0.40
3.0±0.08
3.5±0.18
4a
4b
4c
5a
5b
5c
10a
10b
10c
10d
10e
10f
Streptomycin
Values are expressed as mean±SD (n=3). Values are significant with each other at P<0.05 (Duncan’s multiple range test).
The results indicated that among the tested compounds, concerning
antibacterial activities, compounds 4c, 5a-b, 10b 10d and 10f found
to be potent against E. coli, while the compounds 4a-b, 5c, 10a, 10c
and 10e shown significant activity. The compounds 4a, 5a and 10c-d
found to be potent against K. pneumonia, while the compounds 4b-c,
5b-c, 10a-b and 10e-f shown moderate activity. The compounds 4c,
5a and 10c-d found to be possessed good inhibition against S.
typhimurium, while the compounds 4a-b, 5b-c, 10a-b and 10e-f
shown significant activity as compared with standard drug
streptomycin. From the results, it could be accomplished that, the
chloro and fluoro functioned derivatives showed better activity than
un-substituted derivatives against all bacterial strains.
Antifungal activity
Further, the synthesized compounds were screened for their in vitro
antifungal activity against A. flavusand C. reoformansbecause of their
transmittable nature. The compounds were dissolved in DMSO and
antifungal activity was determined by the poisoned food technique
at concentrations of 50 and 100 μg/ml.
The antifungal result data (table 8) indicated that the synthesized
compounds showed a variable degree of inhibition against fungal
species, the compounds 4c, 5c and 10c-e showed potent activity
against A. flavus, while the compounds 4a-b, 5a-b, 10a-b and 10f
have shown moderate activity.
Table 8: Antifungal activities of substituted [2-(1-benzofuran-2-yl) quinolin-4-yl] methanol and [2-(1-furan-2-yl) quinolin-4-yl] methanol
analogues (4a-c, 5a-c and 10a-f)
Samples code
A. flavus % inhibition
50 µg/ml
36±1.52
45±1.52
56±1.0
42±1.52
47±1.0
56±1.52
34±1.0
41±2.0
51±3.5
53±1.52
57±1.0
46±1.15
47±0.57
C. neoformans % inhibition
100 µg/ml
60±1.0
68±1.0
79±0.57
70±2.08
78±2.0
68±0.57
65±1.52
70±1.15
68±2.0
50 µg/ml
54±1.52
56±3.5
36±1.15
48±1.52
54±1.15
41±1.0
100 µg/ml
4a
4b
4c
5a
5b
5c
10a
10b
10c
86±2.08
80±0.57
85±1.0
76±1.0
87±1.15
84±1.52
90±1.52
86±3.0
71±2.08
86±3.0
54±2.0
50±1.52
36±1.15
54±3.5
10d
10e
10f
74±2.0
78±1.52
82±2.0
68±0.57
44±3.5
42±0.57
80±2.0
74±1.73
75±0.57
Fluconazole
64±2.3
Values are expressed as mean±SD (n=3). Values are significant with each other at P<0.05 (Duncan’s multiple range test).
The compounds 4a-b, 5a-b, 10a-b and 10d showed good activity
against C. reoformans, while the compounds 4c, 5c, 10c and 10f
have showed significant activity when compared with standard
drug fluconazole. The results exhibited that, the halogen-
substituted derivatives showed better activity compared to other
analogues.
Statistical analysis
The measurements were expressed as mean±SD for standard drugs.
The data were analyzed using one-way analysis of variance (ANOVA)
followed by Duncan’s Multiple Range Test (DMRT) by using
statistical package of social science (SPSS) version 10.0 for
151

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Int J Pharm Pharm Sci, Vol 9, Issue 11, 144-153
Windows. A difference in the mean values of P<0.05 was considered
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The present work reports the synthesis, spectral characterization
and biological activities including antioxidant and antimicrobial
activities of synthesized series of benzofuran/furan quinoline
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ADMET/SAR in silico, the synthesized molecules are in an acceptable
range were further screened for antioxidant analysis with DPPH and
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antioxidant and potent antimicrobial activity. The potent molecules
(4b-c, 5a-c, and 10b-f) will be further taken up for in detail study, by
varying the functionalities on the aromatic rings with achange in
carbon chain length, the electron donor and withdrawing groups.
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Dr. N. D. Satyanarayan is the mentor involved in designing and is
the supervisor of the overall work. Mr. Anantacharya R is mainly
involved in synthesis/characterization of entitled molecules and
carried out in silico pharmacokinetic studies and their inter-
pretation. Dr. K M. Mahadevan involved in the idea generation of in
the generation of new coupled heterocyclic analogues; Mr. Sameer
P. was instrumental in carrying out in vitro antimicrobial and
antioxidant results. Mr. Adarsha is helped in generating the
spectral data.
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ACKNOWLEDGEMENT
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seriesofquinoline analogues as potent inhibitors of C.
The authors are thankful to Kuvempu University, for providing
necessary facilities to carry out the present work, one of the authors
(Mr. Anantacharya) is thankful to the DST Government of India, for
awarding Inspire fellowship (IF140251), and the authors are
thankful to Dr. V. H. Kulkarni, Principal, Soniya Pharmacy College
Dharwad, Karnataka, India for providing IR spectral data.
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CONFLICT OF INTERESTS
There is no any conflict of interest
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