Synthesis, antibacterial and anticancer evaluation of 5-substituted (1,3,4-oxadiazol-2-yl)quinoline

Article abstract of DOI:10.1007/s00044-014-1308-2

2-Chloroquinoline-3-carbaldehyde (2) was synthesized via Vilsmeier-Haack method using acetanilide. Phenoxy/naphthalene-1-yl/naphthalen-2-yloxy methyl-1H-benzimidazol-1-yl)acetohydrazide (7a-c) were synthesized using 2-[2-(phenoxy/naphthalen-1-yl/naphthalen-2-yloxy methyl)-1H-benzimidazol-1-yl]acetohydrazide (6a-c). The title compounds 2-chloro-3-{5-[(2-phenoxy/naphthalene-1-yl/naphthalen-2-yloxy methyl-1-H-benzimidazol-1-yl)methyl]-1,3,4-oxadiazol-2-yl}quinolone (8a-c) were prepared using chloramine-T. In the second series, (2-chloroquinolin-3-yl)methylidene]-substituted benzohydrazide (11a-i) were prepared by the reaction of 2-chloroquinoline-3-carbaldehyde (2) and an acid hydrazide (10a-i). The synthesized compounds were characterized by IR, NMR, Mass spectrometry, elemental analysis and screened for their antibacterial (serial dilution technique and disc diffusion method) and anticancer activity by NCI 60 cell screen at a single high dose (10^-5 M) on various panel/cell lines. The synthesized compounds (8a, 8c, 12a, 12b, 12c and 12h) were acting as a magic bullet against gram-positive strains of Bacillus cereus MTCC1305, and the compounds (12a, 12c and 12h) were also found to be extremely active against Klebsiella pneumonia NCTC7447. In the in vitro screen on tested cancer cell line, the compound (12d) showed 95.70 growth percent (GP) and highly active on SNB-75 (CNS cancer) and UO-31 (renal cancer) (GP = 53.35 and 64.35, respectively), and the compound (8a) showed 96.86 GP and highly active on SNB-75 (CNS cancer GP 51.27).

Full text of DOI:10.1007/s00044-014-1308-2

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-014-1308-2
ORIGINAL RESEARCH
Synthesis, antibacterial and anticancer evaluation of 5-substituted
(1,3,4-oxadiazol-2-yl)quinoline
•
Salahuddin Avijit Mazumder Mohammad Shaharyar
•
Received: 14 May 2014 / Accepted: 2 December 2014
ꢀ Springer Science+Business Media New York 2014
Abstract 2-Chloroquinoline-3-carbaldehyde (2) was syn-
thesized via Vilsmeier–Haack method using acetanilide.
Phenoxy/naphthalene-1-yl/naphthalen-2-yloxy methyl-1H-
benzimidazol-1-yl)acetohydrazide (7a–c) were synthesized
using 2-[2-(phenoxy/naphthalen-1-yl/naphthalen-2-yloxy
methyl)-1H-benzimidazol-1-yl]acetohydrazide (6a–c). The
title compounds 2-chloro-3-{5-[(2-phenoxy/naphthalene-1-
yl/naphthalen-2-yloxy methyl-1-H-benzimidazol-1-yl)me-
thyl]-1,3,4-oxadiazol-2-yl}quinolone (8a–c) were prepared
using chloramine-T. In the second series, (2-chloroquinolin-
3-yl)methylidene]-substituted benzohydrazide (11a–i) were
prepared by the reaction of 2-chloroquinoline-3-carbalde-
hyde (2) and an acid hydrazide (10a–i). The synthesized
compounds were characterized by IR, NMR, Mass spec-
trometry, elemental analysis and screened for their antibac-
terial (serial dilution technique and disc diffusion method)
and anticancer activity by NCI 60 cell screen at a single high
dose (10-5 M) on various panel/cell lines. The synthesized
compounds (8a, 8c, 12a, 12b, 12c and 12h) were acting as a
magic bullet against gram-positive strains of Bacillus cereus
MTCC1305, and the compounds (12a, 12c and 12h) were
also found to be extremely active against Klebsiella pneu-
monia NCTC7447. In the in vitro screen on tested cancer cell
line, the compound (12d) showed 95.70 growth percent (GP)
and highly active onSNB-75 (CNS cancer) and UO-31 (renal
cancer) (GP = 53.35 and 64.35, respectively), and the
compound (8a) showed 96.86 GP and highly active on SNB-
75 (CNS cancer GP 51.27).
Keywords 1,3,4-Oxadiazole ꢀ Antibacterial ꢀ
Anticancer ꢀ Quinoline
Introduction
Heterocyclic compounds with nitrogen are considered as
great interest in natural products (Jin, 2003) as they are
used frequently in medicinal chemistry. Among them
oxadiazoles are considered important as there is furan ring
with two methane (–CH=) groups which are replaced by
two pyridine types of nitrogen (–N=) atoms. Four types of
isomers are observed which depend on the position of
nitrogen atoms present in the ring (Somani and Shirodkar,
2009) as described in Fig. 1.
Literature survey reveals that the heterocyclic com-
pounds containing 1,3,4-oxadiazole moiety have been used
as a pi-conjugation which are used to prepare large number
of donor–acceptor molecules that carry a rich pi-electron
aromatic ring. Hence, compounds with 1,3,4-oxadiazole
moiety are considered as a good choice for optical material
or biologically active chemicals (Dabiri et al., 2006) with
various applications like HIV-integrase inhibitor raltegravir
(Steigbigel et al., 2008), furamizole as nitrofuran antibac-
terial (Ogata et al., 1971), antihypertensive agents tiodaz-
osin (Vardan et al., 1983) and nesapidil (Schlecker and
Thieme, 1988), anticancer (Sengupta et al., 2008; Jin et al.,
2006; Holla et al., 2005), anticonvulsant (Almasirad et al.,
2004; Aziz et al., 2009), antimicrobial (Shetgiri and Nayak,
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-014-1308-2) contains supplementary
material, which is available to authorized users.
Salahuddin (&) ꢀ A. Mazumder
Department of Pharmaceutical Technology, Noida Institute of
Engineering and Technology, Greater Noida 201306, Uttar
Pradesh, India
e-mail: sallu_05@yahoo.co.in
M. Shaharyar
Department of Pharmaceutical Chemistry, Faculty of Pharmacy,
Jamia Hamdard (Hamdard University), New Delhi 110062, India
123

Med Chem Res
O
O
O
vomiting, serious infections, hair loss and growth of the
tumour cell population (Isikdag et al., 2011). Thus, our
main aim was to develop a new molecule for antibacterial
and anticancer drugs which can be used as a lead com-
pound for further development.
O
N
N
N
N
N
N
N
N
1,2,3-oxadiazole
1,2,4-oxadiazole
1,2,5-oxazole
1,3,4-oxadiazole
Fig. 1 Isomers of oxadiazole
Materials and methods
2005; Manjunatha et al., 2010; Shailaja et al., 2010;
Mulwad and Chaskar, 2006; Ansari and Lal, 2009), anti-
inflammatory analgesic (Bhandari et al., 2008; Dewangan
et al., 2010; Amir, 2007; Kumar et al., 2008; Jayashankar
et al., 2009), dyes and pigments (Shui et al., 2010),
ulcerogenic (Gilani et al., 2010), antitubercular (Ali and
Shaharyar, 2007) etc. which are based on 1,3,4-oxadiazole
moiety (Fig. 2).
Chemistry
The chemical used for experimental work was commer-
cially procured from various chemical units viz. E. Merck
India Ltd., CDH and S.D. Fine Chem. and Qualigens.
These solvent and reagents were of LR grade and purified
before use. The silica gel G (160–120 mesh) used for
analytical chromatography (TLC) was obtained from E.
Merck India Ltd. Two solvent systems were used, i.e.,
benzene:acetone (9:1 and 8:2) and toluene:ethyl ace-
tate:formic acid (5:4:1). Ashless Whatman no. 1 filter paper
was used for vacuum filtration. Melting points were
determined in open glass capillary using melting point
apparatus and are uncorrected. The 1H NMR and 13C NMR
were recorded on Bruker 300 MHz instrument in DMSO/
CDCl3 using tetramethylsilane [(CH3)4Si] as internal
standard. The infrared spectra of the compound were
recorded in KBr on Perkin-Elmer FTIR spectrometer, and
mass spectra were recorded on API 2000 LC/MS/MS
system. The iodine chamber and UV lamp were used for
visualisation of TLC spots. The commercially available
grades of solvents and reagents were found to be of
A large number of antimicrobial agents show resistance
to clinically significant bacteria which give rise to number
of problems like local irritation, difficulty in wound healing
process, hypersensitivity reactions, systemic toxicity and
the emergence of resistance. So, due to this, the demand of
clinical importance of drug resistant microbial pathogens
has additional led to urgency in microbiological and anti-
fungal research. Cancer treated as proliferation of cells
which occurs in various organs of the body but does not
show any certain etiopathology, so the treatment regime
becomes bit difficult. Hence, different methods are
employed for the treatment of cancer, i.e., immunotherapy,
surgery, radiotherapy and chemotherapy. Cytotoxic agents
play a very important role in the chemotherapeutics, which
reduces the proliferation of malignant cells. The significant
side-effects of chemotherapy are diarrhoea, nausea,
O
O
N+
HN
O-
O
H3C
HN
O
N
H3C
O
N
N
O
N
O
CH3
N
N
O
CH3
F
H3C
Raltegavir
Furamizole
O
O
N
S
O
O
N
O
O
N
N
N
CH3
N
CH3
H3C
H3C
N
O
N
N
N
CH3
Tiodazocin
Nesapadil
Fig. 2 Pharmacologically active compound containing 1,3,4-oxadiazole moiety
123

Med Chem Res
2-(Naphthalene-1-ylmethyl)-1H-benzimidazole
was obtained as white solid, yield 85 %; m.p. 125–126 ꢁC;
IR (KBr) vmax 3,302, 1,528, 2,867 cm-1 1H NMR
(4b) It
adequate purity. However, the presence of undesirable
impurities and others were likely to be used for experi-
mental work was purified/dried.
;
(DMSO, 300 MHz): d = 12.37 (s, 1H, NH), 8.19 (d, 1H,
J = 13.2 Hz, H-50), 7.92 (d, 2H, J = 9.5 Hz, H-6, 9), 7.84
(d, 1H, J = 7.8 Hz, H-80), 7.45 (d, 1H, J = 8 Hz, H-30), 7.
32 (d, 2H, J = 8.3 Hz, H-60, 70), 7.25 (d, 2H, J = 8.5 Hz,
H-7, 8), 7.20 (t, 1H, J = 12.7 Hz, H-20), 7.06 (d, 1H, J =
6.7 Hz, H-10), 4.62 (s, 2H, CH2); 13C NMR (DMSO,
75 MHz): d = 141.5 (C, C-2), 138.1 (C, C-5, 9), 134.2 (C,
C-50), 133.8 (C, C-100), 132.5 (C, C-90), 128.6 (CH, C-60),
127.2 (CH, C-30), 126.9 (CH, C-20, 40), 125.7 (CH, C-70,
80), 124.3 (CH, C-90), 123.1 (CH, C-5, 6), 115.4 (CH, C-5,
8); EIMS m/z: 258.1 (M?); Anal. Calcd. for C18H14N2: C,
83.69; H, 5.46; N, 10.84. Found: C, 83.67; H, 5.49; N, 10.
82.
Synthesis of 2-chloro-quinoline-3-carbaldehyde (2)
2-Chloroquinoline-3-carbaldehyde was synthesized from
acetanilide via Vilsmeier–Haack reaction (Srivatava and
Singh, 2005). To a solution of acetanilide (0.005 mol;
0.67 g) in dry dimethylformamide (0.015 mol; 1.09 ml) at
0–5 ꢁC with stirring, phosphorous oxychloride (0.06 mol;
5.59 ml) was added drop wise and the mixture stirred at
80–90 ꢁC for 12 h. The mixture was poured into crushed
ice and stirred for 5 min, and the resulting solid filtered
was washed well with water and dried. The compound was
purified by recrystallization from ethyl acetate. It was
obtained as yellow solid, yield 65 %; m.p. 146–148 ꢁC; IR
2-[(Naphthalene-2-yloxy)methyl]-1H-benzimidazole (4c) It
was obtained as creamy-white solid, yield 84 %; m.p.
(KBr) vmax 2871, 1687, 749 cm-1 1H NMR (DMSO,
;
300 MHz): d = 10.25 (s, 1H, CHO), 7.70 (t, 1H, J = 6.2,
H-7), 7.25 (d, 1H, J = 6.5 Hz, H-6), 6.89 (d, 1H,
J = 6.3 Hz, H-8), 6.78 (t, 1H, J = 7.1 Hz, H-5); 13C NMR
(DMSO, 75 MHz): d = 190 (CH, –CHO), 153 (C, C-2),
145.4 (CH, C-4), 134 (CH, C-8), 129.8 (C, C-3), 129.3
(CH, C-6), 128.5 (C, C-5), 128 (CH, C-9), 127.2 (CH, C-5);
EIMS m/z: 191.01 (M?); Anal. Calcd. for C10H6ClNO: C,
62.68; H, 3.16; N, 7.31. Found: C, 62.71; H, 3.18; N, 7.33.
205–207 ꢁC; IR (KBr) vmax 3010, 3297, 1464, 1226 cm-1
;
1H NMR (DMSO, 300 MHz): d = 7.70 (d, 2H, J = 5.
4 Hz, H-6, 9), 7.68 (d, 1H, J = 5.6 Hz, H-50), 7.64 (d, 2H,
J = 6.9 Hz, H-30, 80), 7.60 (t, 1H, J = 13.7 Hz, H-70), 7.30
(d, 2H, J = 6 Hz, H-7, 8), 7.47 (t, 1H, J = 15.2 Hz, H-60),
7.30 (s, 1H, J = 5.8 Hz, H-130), 7.26 (s, 1H, H0), 5.34 (s,
2H, CH2O); 13C NMR (DMSO, 75 MHz): d = 155.3 (C,
C-20), 141.7 (C, C-2), 138.2 (C, C-4, 9), 135.2 (C, C-100),
128.2 (C, C-50), 127.8 (CH, C-40), 127 (CH, C-60), 126.7
(CH, C-80), 125.7 (CH, C-80), 123.4 (CH, C-40), 120.5 (CH,
C-6, 7), 119.9 (CH, C-30), 116.4 (CH, C-5, 8), 104.1 (CH,
C-20), 73.4 (CH2, OCH2); EIMS m/z: 274.1 (M?); Anal
Calcd. for C18H14N2O: C, 78.81; H, 5.14; N, 10.21. Found:
C, 78.84; H, 5.15; N, 10.25.
Synthesis of phenoxy/2-naphthalen-1-yl/naphthoxy-methyl-
1H-benzimidazole (4a–c)
A mixture of o-phenylenediamine 3 (0.05 mol; 0.54 g) and
phenoxyacetic acid/naphthylacetic acid/naphthoxyacetic
acid (0.05 mol) was refluxed in 4 N HCl for 4 h on a
heating mantle. After completion of reaction, solution was
poured onto crushed ice; ammonia solution was added drop
wise to neutralize, and the resulting solid was filtered,
washed with cold water, dried and recrystallized with
ethanol.
Synthesis of ethyl 2-(phenoxymethyl/naphthylmethy/
naphthalen-2-yloxy)methyl]-1-yl}acetate (5a–c)
To a suspension of 2-[(phenoxymethyl/naphthylmethy/
naphthalen-2-yloxy)methyl]-1H-benzimidazole (0.01 mol)
and anhydrous potassium carbonate (2 g) in dry acetone,
ethyl chloroacetate (0.01 mol; 1.2 ml) was added drop wise
at room temperature for a period of 20–30 min. The
reaction mixture was stirred at room temperature for
10–12 h. The inorganic solid was filtered off, and filtrate
was concentrated under reduced pressure.
2-Phenoxymethyl-benzimidazole (4a) It was obtained as
yellow solid, yield 80 %; m.p. 160–164 ꢁC. IR (KBr) vmax
3450, 1540, 1240 cm-1 1H NMR (DMSO, 300 MHz)
;
d = 12.31 (s, 1H, NH), 7.70 (d, 1H, J = 9.5 Hz, H-1), 7.47
(d, 1H, J = 9.2 Hz, H-4), 7.29 (t, 2H, J = 14.8 Hz, H-2,
3), 7.19 (s, 2H, H-6, 8), 7.07 (d, 2H, J = 8.7, H-5, 9), 6.85
(t, 1H, J = 12 Hz, H-7), 5.29 (s, 2H, OCH2); 13C NMR
(DMSO, 75 MHz): d = 154.3 (CH2, –CH2O), 142.7 (C,
C-2), 138.9 (C, C-4, 9), 130.1 (CH, C-50), 124.8 (CH, C-30),
124 (CH, C0-4), 123.1 (CH, C-6, 7), 115 (CH, C-5, 8), 112.
3 (CH, C-20, 60); EIMS m/z: 224 (M?); Anal. Calcd. for
C14H12N2O: C, 74.98; H, 5.39; N, 12.49. Found: C, 75.0;
H, 5.35; N, 12.45.
Ethyl [2-(phenoxymethyl)-1H-benzimidazol-1-yl]acetate
(5a) It was obtained as white solid, yield 80 %; m.p.
1
160–164 ꢁC; IR (KBr) vmax 3450, 1540, 1240 cm-1; H
NMR (DMSO, 300 MHz): d = 12.31 (s, 1H, NH), 7.59 (d,
2H, J = 12.3 Hz, H-6, 9), 7.30 (d, 2H, J = 9.7 Hz, H-7,
8), 6.97 (t, 1H, J = 11.5 Hz, H-40), 6.85 (d, 2H, J = 6.
7 Hz, H-20, 60), 5.29 (s, 2H, OCH2), 4.12 (q, 2H, CH2), 2.30
123

Med Chem Res
(t, 3H, J = 12.7 Hz, CH3); 13C NMR (DMSO, 75 MHz):
d = 163.4 (C, C-10), 142.1 (C, C-2), 138.7 (C, C-4, 9), 123.
3 (CH, C-6, 7), 120.1 (CH, C-40), 115.7 (CH, C-5, 8), 114.6
(CH, C-20, 60), 66.7 (CH2, –OCH2), 51.5 (CH2), 14 (CH2, –
CH2CH3); EIMS m/z: 310.1 (M?); Anal. Calcd. for
C14H12N2O: C, 74.98; H, 5.39; N, 12.49. Found: C, 75.0;
H, 5.35; N, 12.45.
mixture was cooled, and the solid so obtained was filtered,
washed with cold water and recrystallized from methanol.
2-[2-(Phenoxymethyl)-1H-benzimidazol-1-yl]acetohydraz-
ide (6a) It was obtained as white solid, yield 80 %; m.p.
178–180 ꢁC; IR (KBr): vmax 3287, 3034, 1656, 1600, 1242,
1030 cm-1 1H NMR (DMSO, 300 MHz): d = 9.43 (s,
;
1H, CONH), 7.69 (d, 2H, J = 12.6 Hz, H-6, 9), 7.31 (d,
2H, J = 12.6 Hz, H-7, 8), 7.18 (d, 2H, J = 6.0 Hz, H-3,
50), 7.02 (t, 1H, J = 9.5 Hz, H-40), 6.92 (d, 2H, J = 6.
2 Hz, H-20, 60), 5.48 (s, 2H, CH2O), 4.90 (s, 2H, CH2), 2.52
(s, 1H, NH2); 13C NMR (DMSO, 75 MHz): d = 169.3 (C,
CONH), 165 (C, C-10), 141.3 (C, C-2), 136.7 (C, 4, 9), 130.
5 (CH, C-30, 122 (CH, C-60, 70), 120.1 (CH, C-40), 113.4
(CH, C-5, 8), 112.1 (CH, C-20, 60), 67.3 (CH2, –OCH2), 51.
9 (CH2, –NCH2). EIMS m/z: 296.1 (M?). Anal. Calcd. for
C16H16N4O2: C, 64.85; H, 5.44; N, 18.91. Found: C, 64.86;
H, 5.42; N, 18.89.
Ethyl [2-(naphthalen-1-ylmethyl)-1H-benzimidazol-1-yl]ace-
tate (5b) It was obtained as white solid, yield 72 %; m.p.
108–112 ꢁC; IR (KBr) vmax 3010, 3206, 1436, 1229 cm-1
;
1H NMR (DMSO, 300 MHz): d = 7.79 (d, 2H, J = 7.
0 Hz, H-6, 9), 7.71 (d, 1H, J = 6.3 Hz, H-60), 7.64 (d, 1H,
J = 4.0 Hz, H-30), 7.60 (d, 1H, J = 4.8 Hz, H-70), 7.55 (d,
2H, J = 7.5 Hz, H-7, 8), 7.50 (t, 1H, J = 9.8 Hz, H-20), 7.
46 (d, 2H, J = 5.8 Hz, H-1060), 5.06 (s, 2H, CH2CO), 4.14
(q, 2H, CH2), 2.31 (t, 3H, J = 15.4 Hz, CH3); 13C NMR
(DMSO, 75 MHz): d = 141.7 (C, C-2), 138.5 (C, C-5, 9),
134.1 (C, C-50), 133.5 (C, C-100), 132.5 (C, C-90), 128.9
(CH, C-20, 40), 128.6 (CH, C-60), 127.2 (CH, C-30), 123.2
(CH, C-7080), 120.5 (CH, C-90), 116.4 (CH, C-5, 8), 50.5
(CH2, –OCH2), 39.4 (CH2), 15.6 (CH2, –CH2CH3); EIMS
m/z: 344.1 (M?); Anal. Calcd. for C22H20N2O2: C, 76.72;
H, 5.85; N, 8.13. Found: C, 76.70; H, 5.88; N, 8.12; O, 9.
29.
2-[2-(Naphthalen-1-ylmethyl)-1H-benzimidazol-1-yl]acet-
ohydrazide (6b) It was obtained as white solid, yield
82 %; m.p. 147–150 ꢁC; IR (KBr) vmax 3302, 3043, 1643,
1
1528, 1233 cm-1; HNMR (DMSO, 300 MHz): d = 9.25
(s, 1H, CONH), 8.15 (d, 2H, J = 11.2 Hz, H-6, 9), 7.58 (d,
1H, J = 9.0 Hz, H-30), 7.64 (d, 2H, J = 9.5 Hz, H-50, 80),
7.35 (d, 2H, J = 7.5 Hz, H-7, 8), 7.30 (d, 2H, J = 8.9 Hz,
H-60, 70), 7.18 (t, 1H, J = 9.2 Hz, H-20), 7.13 (d, 1H, J =
5.6 Hz, H-10), 4.90 (s, 2H, CH2), 2.50 (s, 1H, NH2); 13C
NMR (DMSO, 75 MHz): d = 170.3 (C, CONH), 140.5 (C,
C-2), 138.4 (C, C-4, 9), 134.7 (C, C-100), 133.7 (C, C-90),
133.5 (CH, C-50), 128.4 (CH, C-60, 70), 126.7 (CH, C-30),
126.2 (CH, C-20, 4), 123.9 (CH, C-70, 80), 113.7 (CH, C-5,
8), 53.1 (CH2, –NCH2), 32.1 (CH2); EIMS m/z: 330.4
(M?); Anal. Calcd. for C22H18N4O: C, 72.71; H, 5.49; N,
16.96. Found: C, 72.71; H, 5.50; N, 16.94.
Ethyl {2-[(naphthalen-2-yloxy)methyl]-1H-benzimidazol-1-
yl}acetate (5c) It was obtained as brownish solid, yield
69 %; m.p. 105–109 ꢁC; IR (KBr) vmax 2950, 1736, 1657,
1
1464, 1226 cm-1; H NMR (DMSO, 300 MHz): d = 7.61
(d, 2H, J = 7.8 Hz, H-6, 9), 7.46 (d, 1H, J = 5.5 Hz,
H-50), 7.40 (d, 2H, J = 7.2 Hz, H-3, 80), 7.30 (t, 1H, J =
13.5 Hz, H-70), 7.21 (d, 2H, J = 10.8 Hz, H-7, 8), 7.09 (d,
1H, J = 5.6 Hz, H-20), 7.09 (d, 1H, J = 5.6 Hz, H-20), 6.
98 (t, 1H, J = 11.5 Hz, H-60), 6.90 (s, 1H, H-100), 5.21 (s,
2H, CH2O), 4.72 (q, 2H, CH2), 2.35 (t, 3H, J = 14.4 Hz,
CH3). 13C NMR (DMSO, 75 MHz): d = 171 (C, –CO),
158.1 (C, C-10), 142 (C, C-4, 9), 137.1 (CH, C-60), 129.3
(CH, C-80), 124.8 (CH, C-40), 121.3 (CH, C-6, 7), 115.4
(CH, C-5, 8), 92.45 (CH, C-20), 62.1 (CH2, OCH2), 50.7
(CH2, –CH2CO), 47.5 (CH2), 13.6 (CH2, –CH2CH3); EIMS
m/z 360.1 (M?); Anal. Calcd. for C22H20N2O3: C, 73.32; H,
5.59; N, 7.77. Found: C, 73.29; H, 5.60; N, 7.80.
2-{2-[(Naphthalen-2-yloxy)methyl]-1H-benzimidazol-1-yl}acet-
ohydrazide (6c) It was obtained as white solid, yield 82 %
; m.p. 208–210 ꢁC; IR (KBr) vmax 3292, 3056, 1668, 1466,
1254 cm-1. 1H NMR (DMSO, 300 MHz): d = 9.05 (s, 1H,
CONH), 7.70 (d, 2H, J = 5.7 Hz, H-6, 9), 7.65 (d, 1H,
J = 5.5 Hz, H-50), 7.58 (d, 2H, J = 6.5 Hz, H-30, 80), 7.52
(t, 1H, J = 11.6 Hz, H-70), 7.32 (d, 2H, J = 6 Hz, H-7, 8),
7.17 (t, 1H, J = 12.2 Hz, H-60), 7.03 (s, 1H, J = 4.7 Hz,
H-20), 6.92 (s, 1H, H-100), 5.35 (s, 1H, CH2O), 4.89 (s, 2H,
CH2), 2.53 (s, 1H, NH2); 13C NMR (DMSO, 75 MHz):
d = 170.3 (C, CONH), 158.8 (C, C-20), 142.6 (C, C-2),
138.9 (C, C-4, 9), 133.5 (C, C-100), 130.7 (C, C-50), 130.3
(CH, C-40), 127.6 (CH, C-60), 127.1 (CH, C-90), 126.2 (CH,
C-80), 122.6 (CH, C-7), 120.3 (CH, C-6, 7), 117.8 (CH,
C-30), 109.4 (CH, C-5, 8), 103.8 (CH, C-10), 66.2 (CH2,
CH2O), 51.9 (CH2, NCH2). EIMS m/z: 346.4 (M?); Anal.
Synthesis of 2-[2-(phenoxy/naphthalen-1-yl/naphthalen-2-
yloxy methyl)-1H-benzimidazol-1-yl]acetohydrazide (6a–c)
To an ethanolic solution of ethyl [2-phenoxymethyl/
(naphthalen-1-ylmethyl)/(naphthalen-2-yloxy)methyl]-1H-
benzimidazol-1-yl]acetate (0.01 mol), hydrazine hydrate
(98 %) (0.01 mol; 0.49 ml) was added and the mixture was
refluxed for 3 h. After completion of the reaction, the
123

Med Chem Res
Calcd. for C22H18N4O2: C, 69.35; H, 5.24; N, 16.17.
Found: C, 69.30; H, 5.21; N, 16.21.
(C, C-300), 121.7 (CH, C-6, C-7), 112.1 (CH, C-5, C-8), 52.
1 (CH2, N-CH2), 28.1 (CH2); EIMS m/z: 503.1 (M?);
Anal. Calcd. for C30H22ClN5O: C, 71.49; H, 4.40; N, 13.
90. Found: C, 69.3; H, 4.27; N, 13.49.
Synthesis of phenoxy/naphthalene-1-yl/naphthalen-2-yloxy
methyl-1H-benzimidazol-1-yl)acetohydrazide (7a–c)
[2-(Naphthalen-2-yloxymethyl)-benzoimidazol-1-yl]-acetic
acid (2-chloro-quinolin-3-ylmethylene)-hydrazide (7c) It
was obtained as brownish solid, yield 72 %; m.p.
272–276 ꢁC; IR (KBr) vmax 3307, 2967, 1667, 1555, 1079,
A mixture of (2-phenoxy/naphthalen-1-yl/naphthalen-2-yloxy
methyl)-benzoimidazol-1-yl) acetohydrazide (0.005 mol) and
2-chloroquinoline-3-carbaldehyde (0.005 mol; 0.95 g) in eth-
anol was refluxed for 5 h. After completion of the reaction, the
reaction mixture was concentrated, cooled and poured in ice-
cold water, the precipitate so formed was filtered, dried and
recrystallized to give the desired compound.
744 cm-1 1H NMR (DMSO, 300 MHz): d = 12.12 (s,
;
1H, CONH), 8.43 (s, 1H, N=CH), 8.16 (s, 1H, H-400), 8.08
(d, 1H, J = 10.1 Hz, H-900), 7.78 (d, 1H, J = 7.6 Hz,
H-50), 7.62 (t, 1H, J = 7.9 Hz, H-700), 7.54 (d, 2H, J = 5.
4 Hz, H-30, H-80), 7.43 (t, 1H, J = 10.7 Hz, H-70), 7.35 (d,
2H, J = 6.7 Hz, H-7, H-8), 7.18–7.31 (m, 3H, H-600, H-7,
H-8), 7.17 (t, 1H, J = 15.6 Hz, H-60), 6.98 (d, 1H, J = 5.
5 Hz, H-20), 6.82 (s, 1H, H-100), 5.71 (s, 2H, OCH2), 5.40
(s, 2H, CH2); 13C NMR (DMSO, 75 MHz): d = 173 (C,
CONH), 156.9 (C, C-200), 154.9 (N=CH), 151.1 (C, C-1000),
142.1 (C, C-2), 137.8 (C, C-4, 9), 135.3 (C, C-50, C-100),
129.1 (CH, C-800), 128.2 (CH, C-900), 127.3 (CH, C-700),
126.4 (CH, C-600), 125.7 (C, C-500), 124.9 (C, C-300), 123.7
(CH, C-70, C-80), 121.9 (CH, C-60, C-90), 120.8 (CH, C-6,
C-7), 119.7 (CH, C-30), 112.3 (CH, C-5, C-8), 103.7 (CH,
C-10), 65.7 (CH2, CH2O), 52.2 (CH2, NCH2); EIMS m/z:
519.1 (M?); Anal. Calcd. for C30H22ClN5O2: C, 69.3; H, 4.
26; N, 13.47. Found: C, 69.3; H, 4.27; N, 13.49.
(2-Phenoxymethyl-benzoimidazol-1-yl)-acetic acid (2-chloro-
quinolin-3-ylmethylene)-hydrazide (7a) It was obtained as
yellowish solid, yield 72 %; m.p. 202–206 ꢁC; IR (KBr)
1
vmax 3310, 3107, 1654, 1535, 1081, 723 cm-1; H NMR
(DMSO, 300 MHz): d = 8.94 (s, 1H, CONH), 8.43 (s, 1H,
N=CH), 8.26 (s, 1H, H-400), 8.12 (d, 1H, J = 8.6 Hz,
H-900), 7.97 (d, 2H, J = 6.9 Hz, H-6, H-9), 7.7800(t, 1H,
J = 13.6 Hz, H-800), 7.66 (t, 1H, J = 8.8 Hz, H-7 ), 7.48
(t, 1H, J = 11.6 Hz, H-40), 7.20–7.34 (m, 3H, H-600, H-7,
H-8), 7.06 (d, 2H, J = 8.7 Hz, H-30, H-50), 6.96 (d, 2H,
J = 8.8 Hz, H-20, H-60), 5.66 (s, 2H, CH2O), 5.11 (s, 2H,
CH2); 13C NMR (DMSO, 75 MHz): d = 173.1 (C,
CONH), 163.7 (C, C-10), 154.8 (CH, N=CH), 142.7 (C,
C-2), 138.2 (C, C-4, C-9), 130.4 (CH, C-800), 129.5 (CH,
C-30,C-50), 128.3 (CH, C-900), 126.9 (CH, C-700), 126.7 (C,
C-500), 124.2 (C, C-300), 123.3 (CH, C-6, C-7), 121.8 (CH,
C-40), 115.1 (CH, C-5, C-8), 110.1 (CH, C-20, C-60), 66
(CH2, CH2O), 52.2 (CH2, NCH2); EIMS m/z: 469.1 (M?);
Anal. Calcd. for C26H20ClN5O2: C, 66.45; H, 4.29; N, 14.
90. Found C, 66.39; H, 4.39; N, 14.87.
Procedure for the synthesis of 2-chloro-3-{5-[(2-phenoxy/
naphthalene-1-yl/naphthalen-2-yloxy methyl-1-H-
benzimidazol-1-yl)methyl]-1,3,4-oxadiazol-2-yl}quinoline
(8a-c)
To an ethanolic solution of 2-chloroquinolin-3-yl)methyl-
idene]-2-(2-phenoxy/naphthalene-1-yl/naphthalen-2-yloxy
methyl-1H-benzimidazol-1-yl)acetohydrazide (0.005 mol),
chloramine-T (0.01 mol; 2.27 g) was added. The solution
was refluxed for 4 h, sodium chloride which separated out
during the course of reaction was filtered off. Excess eth-
anol was completely removed from the filtrate by distilla-
tion under reduced pressure, leaving behind a solid mass
which was crystallized from ethanol to give the desired
compound.
(2-Naphthalen-1-ylmethyl-benzoimidazol-1-yl)-acetic acid
(2-chloro-quinolin-3-ylmethylene)-hydrazide (7b) It was
obtained as yellowish solid, yield 72 %; m.p. 232–236 ꢁC;
IR (KBr) vmax 3317, 3107, 1654, 1531, 1078, 733 cm-1
;
1H NMR (DMSO, 300 MHz): d = 12.32 (s, 1H, CONH),
8.33 (s, 1H, N=CH), 8.20 (s, 1H, H-400), 8.15 (d, 1H, J = 8.
1 Hz, H-900), 8.09 (d, 1H, J = 10.2 Hz, H-50), 7.92 (d, 2H,
J = 9.5 Hz, H-6, H-9), 7.63 (t, 1H, J = 8.8 Hz, H-700), 7.
41 (d, 1H, J = 6.3 Hz, H-30), 7.32 (d, 2H, J = 10.3 Hz,
H-60, H-70), 7.20–7.34 (m, 3H, H-600, H-7, H-8), 7.13 (t, 1H,
J = 11.7 Hz, H-20), 6.91 (d, 1 H, J = 6.7 Hz, H-10), 5.16
(s, 2H, CH2), 5.13 (s, 2H, CH2); 13C NMR (DMSO,
75 MHz): d = 173 (C, CONH), 156.1 (C, C–Cl), 153.3
(CH, N=CH), 152.3 (C, C-1000), 142.7 (C, C-2), 137.9 (C,
C-4, C-9), 137.7 (CH, C-400), 134 (C, C-100), 133.1 (C,
C-50), 130.2 (CH, C-800), 128.3 (C, C-900), 127.9 (CH, C-60,
C-90), 126.7 (CH, C-600), 126.4 (CH, C-20, C-30), 126.1
(CH, C-700), 125.7 (C, C-500), 124.1 (CH, C-7, C-8), 122.7
2-Chloro-3-[5-(2-phenoxymethyl-benzoimidazol-1-ylmethyl)-
[1,3,4]oxadiazol-2-yl]-quinoline (8a) It was obtained as
yellowish solid, yield 65 %; m.p. 238–240 ꢁC; IR (KBr)
v
max 2962, 1598, 1231, 1034, 743 cm-1; 1H NMR (DMSO,
300 MHz): d = 8.08 (s, 1H, H-400), 8.02 (d, 1H, J = 6.
6 Hz, H-900), 7.94 (d, 2H, J = 4.8 Hz, H-6, H-9), 7.88 (t,
1H, J = 13.6 Hz, H-800), 7.53 (t, 1H, J = 7.8 Hz, H-700), 7.
55 (t, 1H, J = 10.4 Hz, H-40), 7.18–7.31 (m, 3H, H-600,
H-7, H-8), 7.09 (d, 2H, J = 8.2 Hz, H-30, H-5), 6.91 (d,
123

Med Chem Res
2H, J = 8.4 Hz, H-20, H-60), 5.64 (s, 2H, CH2O), 5.43 (s,
2H, CH2); 13C NMR (DMSO, 75 MHz): d = 166.7 (C,
C-5oxa), 166.2 (C, C-2oxa), 161 (C, C-10), 155.7 (C, C-200),
143.2 (C, C-2), 138.2 (C, C-4, C-9), 130.1 (CH, C-800), 128.
9 (CH, C-30, C-50), 127.8 (CH, C-900), 127.1 (CH, C-700),
125.6 (C, C-500), 124.2 (C, C-300), 122.7 (CH, C-6, C-7),
121.9 (CH, C-40), 113.4 (CH, C-5, C-8), 112.1 (CH, C-20,
C-60), 76.5 (CH2, CH2O), 46.2 (CH2, NCH2); EIMS m/z:
467.1 (M?); Anal. Calcd. for C26H18ClN5O2: C, 66.74; H,
3.88; N, 14.97. Found: C, 66.70; H, 3.82; N, 14.99.
General procedure for the preparation of acid hydrazides
(10a–i)
The appropriate aromatic acids 9a–i (0.01 mol) were dis-
solved in absolute ethanol (10 ml). Hydrazine hydrate
(0.02 mol, 1 ml) and few drops of conc. sulphuric acid
were added. The reaction mixture was refluxed for 6 h. The
resulting solid obtained was filtered, dried and crystallized
from methanol. The completion of reaction was monitored
by thin-layer chromatography and infrared spectropho-
tometer (Jha et al., 2010). (10a: naphthoxy acetic acid
hydrazide; 10b: phenylacetic acid hydrazide; 10c: p-nitro-
benzoic acid hydrazide; 10d: o-chlorobenzoic acid hydra-
zide; 10e: p-chlorobenzoic acid hydrazide; 10f: nicotinic
acid hydrazide; 10g: phenoxyacetic acid hydrazide; 10h:
3,5-dinitrobenzoic acid hydrazide; 10i: salicylic acid
hydrazide.)
2-Chloro-3-[5-(2-naphthalen-1-ylmethyl-benzoimidazol-1-ylme-
thyl)-[1,3,4]oxadiazol-2-yl]-quinoline (8b) It was obtained
as yellowish-white solid, yield 65 %; m.p. 197–200 ꢁC; IR
1
(KBr) vmax 2952, 1588, 1234, 1033, 740 cm-1. H NMR
(DMSO, 300 MHz): d = 8.04 (s, 1H, H-400), 8.01 (d, 2H,
J = 6 Hz, H-800, H-900), 7.96 (d, 1H, J = 9.2 Hz, H-50), 7.
74 (d, 3H, J = 7.8 Hz, H-80, H-6, H-9), 7.61 (t, 1H, J = 8.
6 Hz, H-700), 7.39 (d, 1H, J = 4.8 Hz, H-30), 7.20–7.34 (m,
5H, H-600, H-7, H-8, H-60, H-70), 7.13 (t, 1H, J = 11.2 Hz,
H-20), 6.91 (d, 1 H, J = 6.7 Hz, H-10), 5.54 (s, 2H, CH2), 5.
31 (s, 2H, CH2); 13C NMR (DMSO, 75 MHz): d = 166.8
(C, C-5oxa), 166.3 (C, C-2oxa), 147.7 (C, C-1000), 139.9
(C, C-2), 135.6 (C, C-4, C-9), 134 (C, C-50, C-100), 130.1
(CH, C-400, C-800), 128.6 (C, C-900), 127.9 (CH, C-60, C-90),
127.1 (CH, C-600), 126.5 (CH, C-20, C-30), 126.3 (CH,
C-700), 125.1 (C, C-500), 124.4 (CH, C-70, C-80), 123.1 (C,
C-300), 115.3 (CH, C-6, C-7), 112.3 (CH, C-5, C-8), 45.6
(CH2, N-CH2), 28.4 (CH2); EIMS m/z: 501.13 (M?); Anal.
Calcd. for C30H20ClN5O: C, 71.78; H, 4.02; N, 13.95.
Found: C, 71.82; H, 4.07; N, 13.94.
Procedure for the synthesis of (2-chloroquinolin-3-
yl)methylidene]-substituted benzohydrazide (11a–i)
A mixture of substituted hydrazide 8a–i (0.003 mol) and
2-chloroquinoline-3-carbaldehyde 2 (0.003 mol; 0.57 g) in
ethanol was refluxed for 5 h. After completion of the reac-
tion, the reaction mixture was concentrated, cooled and
poured in ice-cold water; the precipitate so formed was fil-
tered, dried and recrystallized to give the desired compound.
(Naphthalen-2-yloxy)-acetic acid (2-chloro-quinolin-3-
ylmethylene)-hydrazide (11a) It was obtained as yellow-
ish-white solid, yield 67 %; m.p. 236–239 ꢁC; IR (KBr)
1
vmax 3311, 2921, 1605, 1693, 1605, 1500, 741 cm-1; H
NMR (DMSO, 300 MHz): d = 9.03 (s, 1H, CONH), 8.46
(s, 1H, N=CH), 7.95 (d, 1H, J = 9.3 Hz, H-90), 8.28 (s, 1H,
H-40), 8.10 (d, 1H, J = 6 Hz, H-60), 7.73–7.82 (m, 4H,
H-4, H-6, H-9, H-80), 7.68 (s, 1H, H-10), 7.17–7.34 (m, 4H,
H-3, H-7, H-8, H-70), 5.38 (s, 2H, CH2O); 13C NMR
(DMSO, 75 MHz): d = 173.3 (C, CONH), 157 (C, C-20),
155.7 (C, C-2), 153.3 (C, C-100), 139 (CH, C-40), 135.4
(CH, C-5, 10), 130.5 (CH, C-70), 129.5 (CH, C-4), 128.2
(CH, C-6, C-8, C-9), 127.7 (CH, C-60, C-90), 127.1 (CH,
C-70), 126 (C, C-50), 123.3 (C, C-30), 121 (CH, C-7), 117.9
(CH, C-3), 107.4 (CH, C-1), 78.3 (CH2, OCH2); EIMS m/z:
389.0 (M?); Anal. Calcd. for C22H16ClN3O2: C 67.78; H,
4.14; N, 10.78. Found: C, 67.75; H, 4.17; N, 10.81.
2-Chloro-3-{5-[2-(naphthalen-2-yloxymethyl)-benzoimida-
zol-1-ylmethyl]-[1,3,4]oxadiazol-2-yl}-]-quinoline (8c) It
was obtained as white solid, yield 65 %; m.p. 151–156 ꢁC;
IR (KBr) vmax 2952, 1588, 1238, 1023, 729 cm-1 1H
;
NMR (DMSO, 300 MHz): d = 8.54 (s, 1H, H-400), 8.13 (d,
2H, J = 8.1 Hz, H-50, H-900), 7.94 (t, 1H, J = 18.0 Hz,
H-700), 7.56–7.85 (m, 5H, H-7, H-8, H-30, H-70, H-80), 7.
20–7.42 (m, 3H, H-600, H-7, H-8), 6.97 (t, 1H, J = 21 Hz,
H-60), 6.81 (d, 1H, J = 7.2 Hz, H-20), 6.13 (s, 1H, H-100),
5.74 (s, 2H, CH2), 5.53 (s, 2H, CH2); 13C NMR (DMSO,
75 MHz): d = 166.6 (C, C-5oxa), 166.1 (C, C-2oxa), 161
(C, C-20), 155.9 (C, C-200), 150.3 (C, C-1000), 140.5 (C,
C-2), 135.8 (C, C-4, C-9), 130 (C, 50, C-100), 129.1 (CH,
C-8), 128.4 (CH, C-800), 126.7 (C, C-500), 126.3 (C, C-300),
124.9 (CH, C-70, C-80), 121.7 (CH, C-60, C-90), 120.1 (CH,
C-6, 7), 116.7 (CH, C-30), 112.8 (CH, C-5, C-8), 104.7
(CH, C-10), 67.2 (CH2, CH2O), 46.2 (C’H2, NCH2); EIMS
m/z: 517.3 (M?); Anal. Calcd. for C30H20ClN5O2: C, 69.56;
H, 3.89; N, 13.52. Found: C, 69.61; H, 3.91; N, 13.53.
Phenyl-acetic acid (2-chloro-quinolin-3-ylmethylene)-
hydrazide (11b) It was obtained as yellowish solid, yield
65 %; m.p. 212–216 ꢁC; IR (KBr) vmax 3276, 2931, 1665,
1
1602, 1503, 734 cm-1; H NMR (DMSO, 300 MHz): d =
8.54 (s, 1H, CONH), 8.24 (s, 1H, N=CH), 8.01 (d, 1H, J =
10.6 Hz, H-40), 7.93 (d, 1H, J = 8.7 Hz, H-90), 7.69 (t, 1H,
123

Med Chem Res
J = 7.8 Hz, H-80), 7.51 (t, 1H, J = 9.6 Hz, H-70), 7.18 (d,
1H, H-60), 7.10 (t, 2H, J = 12.3 Hz, H-3, H-5), 7.01–7.06
(m, 3H, H-2, H-4, H-6), 4.55 (s, 2H, CH2); 13C NMR
(DMSO, 75 MHz): d = 173.5 (C, CONH), 156 (C, C-20),
153.2 (CH2), 150 (C, C-100), 139.7(CH, C-40), 136.2 (C,
C-1), 132.5 (CH, C-80), 129.5(CH, C-2, C-6), 129 (CH,
C-3, C-5), 128.3 (CH, C-60, C-90), 127 (CH, C-40), 124.1
(C, C-50), 123.2 (CH, C-70), 120.1 (C, C-30), 40.1 (CH2);
EIMS m/z: 323.08 (M?); Anal. Calcd. for C17H11Cl2N3O:
C, 59.32; H, 3.22; N, 12.21. Found: C, 59.30; H, 3.25; N,
12.24.
2H, J = 7.6 Hz, H-2, H-6); 13C NMR (DMSO, 75 MHz):
d = 170 (C, CONH), 158.2 (C, C-20), 154.1 (CH, N=CH),
151 (C, C-100), 138.1 (CH, C-40), 137 (C, C-4), 132.2 (C,
C-1), 130.5 (C, C-80), 129.6 (CH, C-3, C-5), 128.5 (CH,
C-2, C-6), 127.9 (C, C-90), 127.8 (CH, C-60), 125.6 (CH,
C-70), 125.3 (C, C-50), 122.3 (C, C-30); EIMS m/z: 343.02
(M?); Anal. Calcd. for C17H11Cl2N3O: C, 59.32; H, 3.22;
N, 12.21. Found: C, 59.35; H, 3.26; N, 12.23.
Nicotinic acid (2-chloro-quinolin-3-ylmethylene)-hydra-
zide (11f) It was obtained as brownish-yellow solid, yield
62 %; m.p. 224–228 ꢁC; IR (KBr) vmax 3192, 2927, 1633,
1
4-Nitro-benzoic acid (2-chloro-quinolin-3-ylmethylene)-
hydrazide (11c) It was obtained as yellow solid, yield
72 %; m.p. 250–255 ꢁC; IR (KBr) vmax 3305, 2940, 1692,
1502, 1454, 726 cm-1; H NMR (DMSO, 300 MHz): d =
8.92 (s, 1H, CONH), 8.65 (s, 1H, N=CH), 8.41 (d, 1H, J =
9.7 Hz, H-40), 7.78–7.84 (m, 4H, pyridyl), 7.63 (d, 1H,
J = 9.7 Hz, H-90), 7.50 (t, 1H, J = 8.9 Hz, H-80), 7.41 (t,
1H, J = 12.2 Hz, H-70), 7.38 (d, 1H, H-60); 13C NMR
(DMSO, 75 MHz): d = 171.4 (C, CONH), 157.2 (C, C-20),
154 (CH, N=CH), 152.3 (C, C-100), 149.2 (CH, C-4), 138.3
(CH, C-40), 136.6 (CH, C-6), 130.6 (CH, C-80), 129 (CH,
C-2), 127.9 (CH, C-90), 127 (CH, C-60), 126.5 (CH, C-70),
125.2 (C, C-50), 124.7 (CH, C-5), 123.3 (C, C-30); EIMS m/
z: 310.06 (M?); Anal. Calcd. for C16H11ClN4O: C, 61.84;
H, 3.57; N, 18.03. Found: C, 61.80; H, 3.52; N, 18.07.
1
1535, 1460, 756 cm-1; H NMR (DMSO, 300 MHz): d =
8.54 (s, 1H, CONH), 8.20 (s, 1H, N=CH), 8.03 (d, 1H, J =
9.7 Hz, H-40), 7.96 (t, 2H, J = 12.3 Hz, H-3, H-5), 7.88 (d,
1H, J = 8.7 Hz, H-90), 7.71 (t, 1H, J = 7.8 Hz, H-80), 7.51
(t, 1H, J = 9.6 Hz, H-70), 7.26 (d, 2H, J = 5.6 Hz, H-2,
H-6), 7.18 (d, 1H, H-60); 13C NMR (DMSO, 75 MHz):
d = 170.5 (C, CONH), 158.5 (C, C-20), 153.3 (CH2), 151
(C, C-4), 148.8 (C, C-100), 140 (C, C-1), 135.3 (CH, C-40),
130 (CH, C-80), 128.5 (CH, C-2, C-6), 127 (C, C-90), 126.4
(CH, C-60), 126 (CH, C-70), 125.4 (C, C-50), 122.5 (C,
C-30), 120.1 (CH, C-3, C-5); EIMS m/z: 354.5 (M?); Anal.
Calcd. for C17H11ClN4O3: C, 57.65; H, 3.13; N, 15.79.
Found: C, 57.63; H, 3.11; N, 15.83.
Phenoxyacetic acid (2-chloro-quinolin-3-ylmethylene)-
hydrazide (11g) It was obtained as yellowish-brown
solid, yield 67 %; m.p. 26–219 ꢁC; IR (KBr) vmax 3301,
2929, 1694, 1605, 1500, 740 cm-1 1H NMR (DMSO,
;
3,5-Dimethoxy-benzoic acid (2-chloro-quinolin-3-ylmethy-
lene)-hydrazide (11d) It was obtained as yellow solid,
yield 63 %; m.p. 288–292 ꢁC; IR (KBr) vmax 3193, 2950,
1672, 1562, 1501, 794 cm-1; 1H NMR (DMSO, 300 MHz):
d = 9.02 (s, 1H, CONH), 8.56 (s, 1H, N=CH), 7.94 (d, 1H,
J = 10.2 Hz, H-90), 7.66 (t, 1H, J = 7.1 Hz, H-8), 7.52 (t,
1H, J = 8.4 Hz, H-70), 7.41 (d, 1H, H-60), 7.31–7.35 (m, 3H,
H-2, H-4, H-6), 3.78 (s, 3H, 5-OCH3), 3.67 (s, 3H, 3-OCH3);
13C NMR (DMSO, 75 MHz): d = 170.2 (C, CONH), 164
(C, C-3, C-5), 157.1 (CH, CH=N), 153.2 (C, C-100), 136 (CH,
C-40), 132.5 (C, C-1), 130 (C, C-80), 128.5 (C, C-90), 127.5
(CH, C-60), 126.6 (CH, C-70), 125.2 (C, C-50), 122.3 (C,
C-30), 104.6 (CH, C-2, C-6), 102 (CH, C-5), 56 (OCH3);
EIMS m/z: 369.08 (M?); Anal. Calcd. for C19H16ClN3O3: C,
61.71; H, 4.36; N, 11.36. Found: C, 61.75; H, 4.37; N, 11.39.
300 MHz): d = 8.72 (s, 1H, CONH), 8.45 (s, 1H, N=CH),
7.62 (d, 1H, J = 10.3 Hz, H-90), 7.53 (t, 1H, J = 9.4 Hz,
H-80), 7.40 (t, 1H, J = 11.2 Hz, H-70), 7.34 (d, 1H, J = 6.
3, H-60), 7.32 (t, 1H, J = 7.2, H-4), 7.06 (d, 2H, J = 10.2,
H-3, H-5), 6.90 (d, 2H, J = 9.2 Hz, H-2, H-6), 5.01 (s, 1H,
OCH2); 13C NMR (DMSO, 75 MHz): d = 172.8 (C,
CONH), 163.4 (C, C-1), 159 (C, C-20), 154 (CH, N=CH),
150.3 (C, C-100), 138.3(CH, C-40), 130.3 (CH, C-80), 128.5
(CH, C-4), 127.7 (CH, C-90), 126 (CH, C-60), 125.1 (CH,
C-70), 123.5 (C, C-50), 122.6 (C, C-30), 117.4 (CH, C-4),
110.3 (CH, C-2, 6), 78.6 (CH2, OCH2); EIMS m/z: 339.07
(M?); Anal. Calcd. for C18H14ClN3O2: C, 63.63; H, 4.15;
N, 12.37. Found: C, 63.60; H, 4.19; N, 12.31.
3,5-Dinitro-benzoic acid (2-chloro-quinolin-3-ylmethy-
lene)-hydrazide (11h) It was obtained as brownish-yel-
low solid, yield 78 %; m.p. 70–72 ꢁC; IR (KBr) vmax 3305,
4-Chloro-benzoic acid (2-chloro-quinolin-3-ylmethylene)-
hydrazide (11e) It was obtained as yellow solid, yield
72 %; m.p. 198–202 ꢁC; IR (KBr) vmax 3312, 2945, 1675,
2924, 1670, 1504, 1461, 793 cm-1 1H NMR (DMSO,
;
300 MHz): d = 8.87 (s, 1H, CONH), 8.59 (s, 1H, N=CH),
8.22–8.35 (m, 3H, H-2,H-4, H-6), 7.76 (d, 1H, J = 10.
5 Hz, H-90), 7.58 (t, 1H, J = 10.5 Hz, H-80), 7.43 (t, 1H,
J = 10.4 Hz, H-70), 7.26 (d, 1H, J = 6.9 Hz, H-60); 13C
NMR (DMSO, 75 MHz): d = 171.4 (C, CONH), 157.6 (C,
C-20), 154.2 (CH, N=CH), 151.6 (C, C-100), 150 (C, C-3,
1
1534, 1464, 736 cm-1; H NMR (DMSO, 300 MHz): d =
8.62 (s, 1H, CONH), 8.09 (s, 1H, N=CH), 7.91 (d, 1H, J =
8.7 Hz, H-40), 7.82 (t, 2H, J = 11.2 Hz, H-3, H-5), 7.67 (d,
1H, J = 9.4 Hz, H-90), 7.56 (t, 1H, J = 10.6 Hz, H-80), 7.
43 (t, 1H, J = 9.6 Hz, H-70), 7.33 (d, 1H, H-60), 7.20 (d,
123

Med Chem Res
C-5), 138.2 (CH, C-40), 134.7 (C, C-1), 130.5 (CH, C-80),
128.7 (CH, C-2, C-6), 128 (CH, C-90), 127.8 (CH, C-60),
126.4 (CH, C-70), 126 (CH, C-50), 125.5 (C, C-30), 123
(CH, C-4); MS m/z: 399.0 (M?); Anal. Calcd for
C17H10ClN5O5: C, 51.08; H, 2.52; N, 17.52. Found: C, 51.
05; H, 2.48; N, 17.48.
3-(5-Benzyl-1,3,4-oxadiazol-2-yl)-2-chloroquinoline (12b) It
was obtained as yellowish-white solid, yield 73 %; m.p.
178–180 ꢁC; IR (KBr) vmax 2945, 1587, 1299, 1047,
728 cm-1; 1H NMR (DMSO, 300 MHz): d = 8.05 (d, 1H,
J = 10.9 Hz, H-40), 7.90 (d, 1H, J = 9.7 Hz, H-90), 7.67 (t,
1H, J = 9.7 Hz, H-80), 7.45 (t, 1H, J = 13.7 Hz, H-7), 7.
28 (d, 1H, H-60), 7.19 (t, 2H, J = 10.2 Hz, H-3, H-5), 7.
08–7.16 (m, 3H, H-2, H-4, H-6), 4.56 (s, 2H, CH2); 13C
NMR (DMSO, 75 MHz): d = 166.4 (C, C-5oxa), 166 (C,
C-2oxa), 155.4 (C, C-20), 146.4 (C, C-100), 139.5 (C, C-1),
135 (CH, C-40), 131.9 (C, C-30), 130.7 (CH, C-80), 129.5
(CH, C-2, C-6), 128 (CH, C-3, C-5), 127.8 (CH, C-90), 127
(CH, C-60), 126.5 (CH, C-70), 126.1 (C, C-50), 125.3 (CH,
C-4), 35.8 (CH2); EIMS m/z: 321.6 (M?); Anal. Calcd. for
C18H12ClN3O: C, 67.19; H, 3.76; N, 13.06. Found: C, 67.
22; H, 3.81; N, 13.05.
2-Hydroxy-benzoic acid (2-chloro-quinolin-3-ylmethy-
lene)-hydrazide (11i) It was obtained as yellow solid,
yield 60 %; m.p. 171–173 ꢁC; IR (KBr) vmax 3307, 2965,
1664, 1500, 1473, 733 cm-1
;
1H NMR (DMSO,
300 MHz): d = 8.81 (s, 1H, CONH), 8.50 (s, 1H, N=CH),
7.57 (d, 1H, J = 10.5 Hz, H-90), 7.46 (t, 1H, J = 10.7 Hz,
H-80), 7.38 (t, 1H, J = 9.2 Hz, H-70), 7.29 (d, 1H, J = 7.9,
H-60), 6.67–7.23 (m, 4H, H-2, H-3, H-5, H-6); 13C NMR
(DMSO, 75 MHz): d = 171 (C, CONH), 156 (C, C-2,
C-20), 154.2 (CH, N = CH), 151 (C, C-100), 139 (CH,
C-40), 134.3 (CH, C-4), 130.7 (CH, C-80), 129 (CH, C-6),
128.8 (CH, C-90), 127.5 (CH, C-60), 126.3 (CH, C-70), 125.
2 (CH, C-50), 123.3 (C, C-30), 121.4 (CH, C-5), 119.2 (C,
C-1), 117.7 (CH, C-3); EIMS m/z: 325.06 (M?); Anal.
Calcd. for C17H12ClN3O2: C, 62.68; H, 3.71; N, 12.90.
Found: C, 62.62; H, 3.67; N, 12.94.
2-Chloro-3-[5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl]quino-
line (12c) It was obtained as white solid, yield 66 %; m.p.
79–83 ꢁC; IR (KBr) vmax 2916, 1597, 1299, 1043,
748 cm-1; 1H NMR (DMSO, 300 MHz): d = 8.04 (d, 1H,
J = 9.0 Hz, H-40), 7.99 (t, 2H, J = 6.3 Hz, H-3, H-5), 7.88
(d, 1H, J = 8.7 Hz, H-90), 7.63 (t, 1H, J = 8.8 Hz, H-80),
7.52 (t, 1H, J = 9.4 Hz, H-70), 7.28 (d, 2H, J = 14.6 Hz,
H-2, H-6), 7.20 (d, 1H, J = 6.6 Hz, H-60); 13C NMR
(DMSO, 75 MHz): d = 166.9 (C, C-5oxa), 166.5 (C,
C-2oxa), 156 (C, C-20), 147.5 (C, C-100), 145.8 (C, C-4),
141 (C, C-1), 135.2 (CH, C-40), 132.7 (C, C-30), 131.7 (CH,
C-80), 129.3 (CH, C-90), 128.7 (CH, C-2, C-6), 127.9 (CH,
C-60), 127 (CH, C-70), 126.5 (C, C-5), 123.2 (CH, C-3,
C-5); EIMS m/z: 352.02 (M?); Anal. Calcd. for
C17H9ClN4O3: C, 57.89; H, 2.57; N, 15.88. Found: C, 57.
92; H, 2.55; N, 15.90.
Procedure for the synthesis of 2-chloro-3-(5-substituted-
phenyl-1,3,4-oxadiazol-2-yl)quinoline (12a–i)
To an ethanolic solution of (2-chloroquinolin-3-yl)meth-
ylidene]-substituted benzohydrazide 11a–i (0.002 mol;
0.78 g), chloramine-T (0.004 mol; 0.90 g) was added. The
solution was refluxed for 4 h, sodium chloride which sep-
arated out during the course of reaction was filtered off.
Excess ethanol was completely removed from the filtrate
by distillation under reduced pressure, leaving behind a
solid mass which was crystallized from ethanol to give the
desired compound.
2-Chloro-3-[5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-2-
yl]quinoline (12d) It was obtained as brownish solid,
yield 66 %; m.p. 171–175 ꢁC; IR (KBr) vmax 2926, 1527,
1
1280, 1092, 714 cm-1; H NMR (DMSO, 300 MHz): d =
2-Chloro-3-{5-[(naphthalen-2-yloxy)methyl]-1,3,4-oxadiazol-
2-yl}quinoline (12a) It was obtained as brownish solid,
yield 76 %; m.p. 147–150 ꢁC; IR (KBr) vmax 2916, 1597,
7.71 (d, 1H, J = 12 Hz, H-90), 7.60 (t, 2H, J = 8.7 Hz,
H-70, H-80), 7.46 (d, 1H, J = 7.1 Hz, H-60), 7.26–7.36 (m,
3H, H-2, H-4, H-6), 3.43 (s, 3H, 5-OCH3), 3.33 (s, 3H,
3-OCH3); 13C NMR (DMSO, 75 MHz): d = 167.2 (C,
C-5oxa), 167 (C, C-2oxa), 163 (C, C-3, C-5), 155 (C, C-20),
147 (C, C-100), 141.3 (C, C-1), 135.6 (CH, C-40), 132.4 (C,
C-30), 131 (CH, C-80), 128.9 (CH, C-90), 128.4 (CH, C-60),
128 (CH, C-70), 126.5 (C, C-50), 104 (CH, C-2, 6), 100.7
(CH, C-4), 56 (C, 2-OCH3); EIMS m/z: 367 (M?); Anal.
Calcd. for C19H14ClN3O3: C, 62.05; H, 3.84; N, 11.43.
Found: C, 62.09; H, 3.80; N, 11.40.
1
1297, 1045, 749 cm-1; H NMR (DMSO, 300 MHz): d =
8.49 (s, 1H, H-90), 8.23 (s, 1H, H-40), 8.02 (d, 1H, J =
6 Hz, H-60), 7.67–7.80 (m, 4H, H-4, H-6, H-9, H-80), 7.63
(s, 1H, H-1), 7.12–7.37 (m, 4H, H-3, H-7, H-8, H-70), 4.90
(s, 2H, CH2O); 13C NMR (DMSO, 75 MHz): d = 166.7
(C, C-5oxa), 166.5 (C, C-2oxa), 157.1 (C, C-2), 154.2 (C,
C-20), 146.7 (C, C-100), 136.6 (CH, C-40), 135 (C, C-10),
131.9 (C, C-30), 130.6 (CH, C-80), 129.8 (CH and C, C-4,
C-5), 127.5 (CH, C-90), 126.9 (CH, C-6, C-9), 126.5 (CH,
C-60), 126 (CH, C-70), 125.1 (C, C-50), 123 (CH, C-7, C-8),
115.5 (CH, C-3), 102.5 (CH, C-1), 70.2 (CH2); EIMS m/z:
387 (M?); Anal. Calcd. for C22H14ClN3O2: C, 68.13; H, 3.
64; N, 10.83. Found: C, 68.10; H, 3.65; N, 10.86.
2-Chloro-3-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]quin-
oline (12e) It was obtained as yellowish-white solid,
yield 63 %; m.p. 217–221 ꢁC; IR (KBr) vmax 2906, 1531,
123

Med Chem Res
1289, 1108, 721 cm-1; H NMR (DMSO, 300 MHz): d =
7.89 (d, 1H, J = 9.4 Hz, H-40), 7.76 (t, 2H, J = 11.7 Hz,
H-3, 5), 7.59 (d, 1H, J = 10.7 Hz, H-90), 7.49 (t, 1H, J =
12.3 Hz, H-80), 7.38 (t, 1H, J = 8.9 Hz, H-70), 7.29 (d, 1H,
J = 9.5 Hz, H-60), 7.17 (d, 2H, J = 7.9 Hz, H-2, H-6); 13C
NMR (DMSO, 75 MHz): d = 165.7 (C, C-5oxa), 165.4 (C,
C-2oxa), 155 (C, C-20), 147.8 (C, C-100), 134.6 (CH, C-40),
133.5 (C, C-1), 132.5 (C, C-4), 131.7 (C, C-30), 130.6 (CH,
C-80), 129.8 (CH, C-3, C-5), 129 (CH, C-90), 128.6 (CH,
C-2, C-6), 127 (CH, C-60), 126.9 (CH, C-70), 126.3 (C,
C-50); EIMS m/z: 341 (M?); Anal.Calcd. for C17H9Cl2N3O:
C, 59.67; H, 2.65; N, 12.28. Found: C, 59.73; H, 2.69; N,
12.31.
H-70), 7.27 (d, 1H, J = 6.6, H-60); 13C NMR (DMSO,
75 MHz): d = 166.5 (C, C-5oxa), 166.1 (C, C-2oxa), 156
(C, C-20), 150.4 (C, C-3, C-5), 147 (C, C-100), 137.5 (C,
C-1), 133 (CH, C-40), 130.7 (CH, C-80), 129.4 (CH, C-90),
128.6 (CH, C-2, C-6), 127.7 (CH, C-60), 127 (CH, C-70),
126.1 (C, C-50), 115.6 (CH, C-4); EIMS m/z: 397.1 (M?);
Anal. Calcd. for C17H8ClN5O5: C, 51.34; H, 2.03; N, 17.
61. Found: C, 51.37; H, 2.06; N, 17.64.
1
2-[5-(2-Chloroquinolin-3-yl)-1,3,4-oxadiazol-2-yl]phenol (12i) It
was obtained as yellowish-white solid, yield 63 %; m.p.
141–143 ꢁC; IR (KBr) vmax 3365, 2987, 1595, 1299, 1098,
723 cm-1 1H NMR (DMSO, 300 MHz): d = 10.21 (s,
;
OH, 1H), 7.51 (d, 1H, J = 7 Hz, H-90), 7.41 (t, 1H, J = 10.
3 Hz, H-80), 7.32 (d, 1H, J = 7.0 Hz, H-70), 7.12 (t, 1H,
J = 8.4, H-60), 6.57–6.97 (m, 4H, H-2, H-3, H-5, H-6); 13C
NMR (DMSO, 75 MHz): d = 166.8 (C, C-5oxa), 166.3 (C,
C-2oxa), 157 (C, C-20), 147 (C, C-100), 136.9 (CH, C-40),
132.2 (C, C-30), 131 (CH, C-80), 130 (CH, C-90), 129.5
(CH, C-4, C-6), 127.9 (CH, C-60), 127.2 (CH, C-70), 126.1
(C, C-50), 122.7 (C, C-1), 119.5 (CH, C-5), 115 (CH, C-3);
EIMS m/z: 323.4 (M?); Anal. Calcd. for C17H10ClN3O2: C,
63.07; H, 3.11; N, 12.98. Found: C, 63.11; H, 3.13; N, 12.
95.
2-Chloro-3-[5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl]quinoline
(12f) It was obtained as white solid, yield 58 %; m.p.
135–136 ꢁC; IR (KBr) vmax 3046, 1526, 1299, 1096,
702 cm-1; 1H NMR (DMSO, 300 MHz): d = 8.29 (d, 1H,
J = 10.2 Hz, H-40), 7.72–7.85 (m, 4H, Hpyr), 7.60 (d, 1H,
J = 9.4 Hz, H-90), 7.48 (t, 1H, J = 8.7 Hz, H-80), 7.38 (t,
1H, J = 12 Hz, H-70), 7.32 (d, 1H, J = 7.5 Hz, H-60); 13C
NMR (DMSO, 75 MHz): d = 166.7 (C, C-5oxa), 166.2 (C,
C-2oxa), 154.5 (C, C-20), 149.3 (CH, C-2pyr), 148.1 (CH,
C-4pyr), 146.6 (C, C-100), 136.2 (CH, C-40), 134.2 (CH,
C-6pyr), 133.2 (C, C-1pyr), 132.2 (C, C-30), 131 (CH,
C-80), 129.6 (CH, C-90), 128.5 (CH, C-60), 127.1 (CH,
C-70), 126.2 (C, C-50), 123 (CH, C-5pyr); EIMS m/z: 308.5
(M?); Anal. Calcd. for C16H9ClN4O: C, 62.25; H, 2.94; N,
18.15. Found: C, 62.21; H, 2.98; N, 18.14.
Antibacterial activity
Determination of minimum inhibitory concentration
by serial dilution technique
2-Chloro-3-[5-(phenoxymethyl)-1,3,4-oxadiazol-2-yl]quin-
olone (12g) It was obtained as yellowish-white solid,
yield 66 %; m.p. 167–170 ꢁC; IR (KBr) vmax 2934, 1577,
The stock solutions of synthesized compounds were
reconstituted with a minimum amount of dimethyl sulf-
oxide (DMSO). This solvent did not possess any antimi-
crobial activity of its own. Calculated volume of this stock
solution were dispensed in a series of McCartney bottles
previously containing calculated volume of sterile cooled
molten nutrient agar media (40–45 ꢁC) to prepare final
volume of 30 ml each with dilutions of 5, 12.5, 25, 50, 100,
200 and 400 lg/ml. Then these molten media containing
varying concentration of compounds were poured asepti-
cally in pre sterilized petridishes (70 mm) to give sterile
nutrient agar plates with varying dilution of the com-
pounds. These plates were then kept in the refrigerator at
4 ꢁC for 24 h to ensure uniform diffusion of compounds.
Then these plates were dried at 37 ꢁC before spot inocu-
lations. One loopful culture (loop diameter: 6 mm) of an
overnight grown bacterial strains suspension (105 CFU/ml)
was added in each quadrant as marked by checkerboard
technique. The spotted plates were incubated at 37 ꢁC for
24 h in an incubator, and MIC values were obtained
(Asamenew et al., 2011; Mazumder et al., 2004).
1
1297, 1039, 739 cm-1; H NMR (DMSO, 300 MHz): d =
7.58 (d, 1H, J = 8.7 Hz, H-90), 7.53 (t, 1H, J = 9.2 Hz,
H-80), 7.47 (t, 1H, J = 10.8 Hz, H-70), 7.42 (d, 1H, J = 7.
1, H-60), 7.37 (t, 1H, J = 11.2, H-4), 7.12 (d, 2H, J = 13.2,
H-3, H-5), 6.79 (d, 2H, J = 9.8 Hz, H-2, H-6), 5.94 (s, 1H,
OCH2); 13C NMR (DMSO, 75 MHz): d = 167.7 (C,
C-5oxa), 167 (C, C-2oxa), 161.6 (C, C-1), 157 (C, C-20),
147 (C, C-100), 137.8 (CH, C-40), 132.4 (C, C-30), 131.1
(CH, C-80), 130 (CH, C-90), 129.2 (CH, C-3, 5), 128 (CH,
C-60), 126.4 (CH, C-70), 124.5 (C, C-50), 120.1 (CH, C-4),
114 (CH, C-2, 6), 75.1 (OCH2); EIMS m/z: 337.6 (M?);
Anal. Calcd. for C18H12ClN3O2: C, 64.01; H, 3.58; N, 12.
44. Found: C, 64.05; H, 3.61; N, 12.47.
2-Chloro-3-[5-(3,5-dinitrophenyl)-1,3,4-oxadiazol-2-yl]quin-
oline (12h) It was obtained as yellow solid, yield 76 %;
m.p. 134–135 ꢁC; IR (KBr) vmax 3047, 1597, 1298, 1095,
1
703 cm-1; H NMR (DMSO, 300 MHz): d = 8.22–8.38
(m, 3H, H-2, H-4, H-6), 7.84 (d, 1H, J = 10.2 Hz, H-90), 7.
61 (t, 1H, J = 12.2 Hz, H-80), 7.43 (t, 1H, J = 10.5 Hz,
123

Med Chem Res
Determination of zones of inhibition of disc diffusion
method
Percentage growth inhibition is calculated as
½ðTi ꢁ TzÞ=ðC ꢁ TzÞꢂ ꢃ 100 for concentrations for which Ti ꢄ Tz
½ðTi ꢁ TzÞ=Tzꢂ ꢃ 100 for concentrations for which Ti\Tz:
A 200 lg/ml solution of both synthesized compounds and
ciprofloxacin (solvent: DMSO) were prepared in sterilized
McCartney bottles. Sterile molten media plates were pre-
pared and incubated at 25 ꢁC for 24 h to check for the
presence of any sort of contamination. Then each sterilized
nutrient agar plates were flooded with liquid culture of
bacterial strains and dried for 30 min at 25 ꢁC. The sterile
Whatman filter paper disc (4-mm diameter) was soaked in
solution of synthesized compounds and placed in appro-
priate position of the plates marked as quadrant at the back
of petridishes. All the flooded plates with corresponding
paper discs soaked with solution of synthesized compounds
were incubated at 25 ꢁC for 24 h, and diameter of zone of
inhibition was measured in mm. Similar procedure was
adopted for ciprofloxacin, and corresponding zone diame-
ters were measured and compared accordingly.
All values are statistically analysed and are expressed as
mean with a range of growth for various cell lines.
Results and discussion
Synthesis
2-Chloroquinoline-3-carbaldehyde (2) was prepared from
acetanilide via Vilsmeier–Haack approach. In Scheme 1,
the
2-[2-(phenoxy/naphthalen-1-yl/naphthalen-2-yloxy
methyl)-1H-benzimidazol-1-yl]acetohydrazide (6a–c) were
prepared using o-phenylenediamine and the corresponding
acid by a series of step (Salahuddin et al., 2014a). The
phenoxy/naphthalene-1-yl/naphthalen-2-yloxy methyl-1H-
benzimidazol-1-yl)acetohydrazide (7a–c) were prepared
using 2-chloroquinoline-3-carbaldehyde (2) and 2-[2-
(phenoxy/naphthalen-1-yl/naphthalen-2-yloxymethyl)-1H-
benzimidazol-yl]acetohydrazide (6a–c) in the presence of
ethyl alcohol. The syntheses of 2-chloro-3-{5-[(2-phenoxy/
naphthalene-1-yl/naphthalen-2-yloxy methyl-1-H-benzimi-
dazol-1-yl)methyl]-1,3,4-oxadiazol-2-yl}quinolone (8a–
c) were prepared using chloramine-T. In Scheme 2, the
different hydrazide (10a–i) were synthesized using differ-
ent aromatic acids (Jha et al., 2010). The (2-chloroquino-
line-3-yl)methylidene]-substituted benzohydrazide (11a–
i) were synthesized by reacting with 2-chloroquinoline-3-
carbaldehyde (2) and the different hydrazide (10a–i). In the
final step, 2-chloro-3-(5-substituted-phenyl-1,3,4-oxa-
diazol-2-yl)quinoline (12a–i) were synthesized with chlo-
ramine-T as the titled compounds. In general, the IR
spectra of the compounds 7a, 7b and 7c showed absorption
peaks of C=O at 1654, 1654 and 1667 and NH peaks at
3310, 3317 and 3307, respectively. 1H NMR spectra of the
compounds 7a, 7b and 7c show singlet between d5 and d6
of CH2 and CH2O respectively. The Schiff bases
(7a–c) explained the presence of –CONH and –N=CH from
the presence of two singlet between d8 and d9. In IR
spectra of the compounds 8a–c, disappearance of C=O and
NH peaks indicates the formation of desired compounds.
1H NMR spectra of the compounds 8a–c also show two
singlet between d5 and d6 of CH2 and CH2O respectively.
In Scheme 2, compounds 11a–i show two absorption peaks
of C=O and –NH in IR spectra, and these two peaks were
absent in the compounds 12a–i confirm the formation of
oxadiazole. The 13C NMR spectra of 1,3,4-oxadiazole
(8a–c and 12a–i) shows two peaks between 165 and 168.
Anticancer activity
Treatment of tumour cell lines
All compounds were submitted to the National Cancer
Institute, and three compounds were selected for anticancer
screening on NCI 60 cell lines initially at a single high dose
(10-5 M) on leukaemia (CCRF-CEM, HL-60 (TB), K-562,
MOLT-4, RPMI-8226, SR), non-small cell lung cancer
(A549/ATCC, HOP-62, HOP-92, NCI-H226, NCI-H23,
NCI-H322M, NCI-H460, NCI-H522), colon cancer (COLO
205, HCC-2998, HCT-116, HCT-15, HT29, KM12, SW-
620), CNS cancer (SF-268,SF-295,SF-539,SNB-19, SNB-
75), melanoma (LOX IMVI, MALME-3M, M14, MDA-
MB-435, SK-MEL-2, SK-MEL-28, SK-MEL-5, UACC-
257, UACC-62), ovarian cancer (IGROV1, OVCAR-3,
OVCAR-4, OVCAR-5, OVCAR-8 NCI/ADR-RES 99.24,
SK-OV-3), renal cancer (786-0, A498, ACHN, CAKI-1,
SN12C, TK-10, UO-31), prostate cancer (PC-3, DU-145)
and breast cancer (MCF7, MDA-MB-231/ATCC, HS
578T, BT-549, T-47D, MDA-MB-468) cell lines, nearly 60
in number. The One-dose data were reported as a mean
graph of the percent growth of treated cells. The number
reported for the one-dose assay is growth relative to the no-
drug control, and relative to the time zero number of cells.
The anticancer screening was carried out as per the NCI US
protocol reported elsewhere (http://dtp.nci.nih.gov; Monks
et al., 1991; Boyd and Paull, 1995; Shoemaker, 2006).
Using the seven absorbance measurements [time zero (Tz),
control growth (C), and test growth in the presence of drug
at the five concentration levels (Ti)], the percentage growth
was calculated at each of the drug concentrations levels.
123

Med Chem Res
CHO
Cl
POCl3, DMF
80-900C
N
NHCOCH3
(2)
(1)
NH2
N
N
N
N
N
NH2NH2,H2O
EtOH
4N HCl, Reflux
ClCH2COOC2H5
R
R
R
RCOOH
dry acetone, K2CO3
N
H
NH2
CH2COOC2H5
(3)
CH2CONHNH2
(5a-c)
(6a-c)
(4a-c)
N
N
N
CHO
Cl
R
EtOH
R
+
N
Reflux
H
N
N
N
N
CH2CONHNH2
(2)
(6a-c)
Cl
O
(7a-c)
Reflux
EtOH, Chloramine-T
N
N
R
O
N
N
(8a-c)N
R= Phenoxymethyl. naphthylmethyl. napthoxymethyl
Cl
Scheme 1 Protocol for the synthesis of title compounds (8a-c)
(i) EtOH, H2SO4
R'CONHNH2
R'COOH
(ii)
NH2NH2.H2O, Reflux
(10a-i)
(9a-i)
O
O
N
N
H
EtOH. Reflux
+
R'
N
H
R'CONHNH2
(10a-i)
Cl
N
Cl
(11a-i)
(2)
Reflux
EtOH, Chloramine-T
R'
O
N
N
N
Cl
(12a-i)
R'= naphthoxymethyl, benzyl, 4-nitrophenyl, 3,5-dimethoxyphenyl, 4-chlorophenyl, nicotinyl, phenoxymethyl, 3,5-dinitrophenyl, 2-
hydroxyphenyl.
Scheme 2 Protocol for the synthesis of title compounds (12a-i)
Antibacterial activity
magic bullet against various gram-positive strains of
Bacillus cereus MTCC1305 as they were inhibited at very
low concentration of the compounds. The compound 12c
was as potent as pure ciprofloxacin against B. cereus
It was observed that the maximum number of synthesized
compounds (8a, 8c, 12a, 12b, 12c and 12h) was acting as
123

Med Chem Res
123

Med Chem Res
Anticancer activity (Salahuddin et al., 2014b)
MTCC1305. The synthesized compounds (12a, 12c and
12h) were also found to be extremely active against
Klebsiella pneumonia NCTC7447, and hence they may be
regarded as potent-promising agent for controlling pneu-
monia. It was also noted that 8c and 12f were very
instrumental in inhibiting most of the pathogenic multidrug
resistant of various gram-negative species including E. coli
35B, Vibrio cholera 765 and Proteus vulgaris AP169.
Compounds 8b and 12b were having a MIC of 50 lg/ml
against Acetobacter aceti AP586 and Mongonella morganii
ATCC 25830 when tested. Shigella sonnei E08869, Pseu-
domonas putida MTCC 2252 and Shigella dysenteriae 9
found to show significant degree of resistance against
majority of synthesized compounds; however, both the
strains of S. dysenteriae 9 and S. sonnei E08869 were
effectively controlled by the synthesized compound (12f)
at a concentration as low as 50 lg/ml (Table 1). Thus, we
observe from our study that these compounds have a fairly
broad spectrum of antibacterial efficacy and hence may be
regarded as a potent candidate to control the global thread
of drug resistant in future.
The synthesized compounds displayed moderate to low
activity in the in vitro screen on all tested cancer cell lines
and are given in Table 3. The compounds 8a and 12d were
found to be the most active compound of the series and
much better growth interaction as compared to 12f against
SNB-75. The compound 12d showed 95.70 growth percent
(GP) and highly active on SNB-75 (CNS cancer), UO-31
and CAKI-1 (renal cancer) (GP = 53.35, 64.35, and 77.71,
respectively), and the compound 8a showed 96.86 GP and
highly active on SNB-75 (CNS cancer), UO-31 (renal
cancer) and IGROV1 (ovarian cancer) with GP of 51.27,
67.58 and 77.85, while compound 12f showed maximum
sensitivity on SNB-75 (CNS cancer) with GP of 60.89. The
compounds 8a, 12d and 12f were found to be highly sen-
sitive on SNB-75 and UO-31. The GP and percent growth
inhibition (GI) of these compounds are shown in Fig. 3.
The maximum percent growth inhibition was recorded for
SNB-75 with GP of 51.27 and percent GI of 48.73.
Structure activity relationship (SAR)
The disc diffusion study reveals that the diameter of
zone of inhibition was in coherence with the study of MIC
conducted on various synthesized compounds against the
selected microorganisms. It was observed that compound
with lower MIC showed a great zone of inhibition against
all the test microorganisms. Compounds (8a, 8c, 12a, 12b,
12c and 12h) was found to be most active against gram-
positive bacteria particularly B. cereus MTCC1305 show-
ing zone of inhibition 9.5–11 mm. Compounds 12a, 12c
and 12h were found to be most active against K. pneu-
monia NCTC7447 and it shows zone of inhibition MIC of
12.5 lg/ml and maximum zone of inhibition 10.5, 10 and
11 mm, respectively (Table 2).
On the basis of our findings, we could analyse the fol-
lowing points for antibacterial and anticancer activities:
•
The compounds having 1,3,4-oxadiazole carrying
benzimidazole moiety have better antibacterial activity
(8a and 8c) and anticancer activity (8a) than those of
the compounds having only 1,3,4-oxadiazole moiety.
Groups like 2-phenoxy-methyl/2-naphthoxymethyl and
naphthoxymethyl benzimidazole shown good antibac-
terial activity.
•
•
The antibacterial activity was improved due to the
presence of electron withdrawing groups viz. 4-nitro,
Table 3 Anticancer activities of selected compound by NCI
Compounds
Sixty cell lines assay in one dose 10-5 M conc.
NSC
code
Mean
growth %
Range of
growth %
The most sensitive cell line
Growth % of the
most sensitive cell line
8a
772520
772522
772521
96.86
95.70
51.27–123.33
53.35–104.73
60.89–119.03
SNB-75 (CNS Cancer)
UO-31 (renal cancer)
51.27
67.58
77.85
53.35
64.35
77.71
60.89
81.23
82.81
IGROV1 (ovarian cancer)
SNB-75 (CNS cancer)
UO-31 (renal cancer)
12d
12f
CAKI-1(renal cancer)
101.07
SNB-75 (CNS cancer)
NCI-H522 (non-small cell lung cancer)
UO-31 (renal cancer)
The growth percentage depicted in Table 2 reveals the mean values of triplicate readings. All the values are statistically analysed and are
expressed as mean with a range of growth for various cell lines
123

Med Chem Res
Fig. 3 The growth percent
(GP) and percent growth
inhibition (GI) of the
compounds 8a, 12d, and 12f on
most sensitive cell lines
90
80
70
60
50
40
30
20
10
0
GP
% GI
8a
12d
12f
activity of new 2-substituted-5-[2-(2-fluorophenoxy)phenyl]-
1,3,4-oxadiazoles and 1,2,4-triazoles. Bioorg Med Chem Lett
14:6057–6059
3,5-dinitro and 4-chloro (12a, 12c and 12h)-substituted
phenyl on 1,3,4-oxadiazole ring against B. cereus
MTCC1305 and K. pneumonia NCTC7447.
The compound having electron-releasing substituent
like 3,5-dimethoxy and nicotinyl (12d and 12f) has
better anticancer activity, i.e. GP of the most sensitive
cell lines.
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•
Conclusion
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Two series of 2,5-disubstitutedoxadiazole (8a–c and
12a–i) were synthesized successfully by the Schiff base
(7a–c and 11a–i) with chloramine-T. Among the synthe-
sized compound mainly 1,3,4-oxadiazole derivatives (8a,
8c, 12a, 12b, 12c and 12h) emerged as lead compounds,
these compounds showed good antibacterial activity with
MIC 12.5 and 25 lg/ml. The compounds 8a, 12d and 12f
showed significant anticancer activity which can be further
modified to exhibit better potency.
Acknowledgments The authors are so much grateful to Managing
Director NIET for providing the research facilities and IIT Delhi for
providing the spectral data. The authors also wish to express their
thanks to all the staffs of National Cancer Institute, Bethesda, MD,
USA for in vitro evaluation of anticancer activity. We would also like
to thanks Dr Jawed Ahsan, Dr. G.S. Chakraborthy, Mr. Vikas Rat-
hore, Ms. Sangita Kumari and Mr. Rajnish Kumar for the kind sup-
port for preparing the manuscript.
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