Synthesis and biological evaluation of novel benzothiazole clubbed fluoroquinolone derivatives

Article abstract of DOI:10.3109/14756366.2011.611943

In the present investigation, synthesis and anti-bacterial, analgesic and anthelmintic evaluation of a novel series of fluoroquinolone derivatives clubbed with benzothiazole moeity has been described. The synthesized compounds were characterised by spectral analysis (IR and H NMR). Preliminary results indicated that the most of the synthesized compounds demonstrated good activities against gram negative and gram positive bacterial strains. Compounds 5a, 5b, 5f and 5k demonstrated potent anti-bacterial activities. Compound 5a exhibited most potent anti-bacterial activity with MIC values of 04, 03, 08 and 15 μg/ mL against B. subtilis, S. aureus, E. coli and P. aeruginosa. Analogs 5a, 5c, 5g and 5h showed promising anthelmintic activity against Eisemia foetida in a low concentration as compared to standard drug piperazine citrate with mean paralysis time ranging 22.60 ± 2.46 to 31.60 ± 3.07 min. All synthesized compounds depicted good in vivo analgesic activity with compound 5a exhibiting the most potent activity of 55.19% inhibition of writhing in comparison to the standard drug.

Full text of DOI:10.3109/14756366.2011.611943

Journal of Enzyme Inhibition and Medicinal Chemistry, 2013; 28(1): 1–10
© 2013 Informa UK, Ltd.
ISSN 1475-6366 print/ISSN 1475-6374 online
DOI: 10.3109/14756366.2011.611943
RESEARCH ARTICLE
Synthesis and biological evaluation of novel benzothiazole
clubbed fluoroquinolone derivatives
Prabodh Chander Sharma1, Ravinder Kumar1, Monika Chaudhary1, Archana Sharma1,
and Harish Rajak2
1Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra, India and 2Institute of Pharmaceutical
Sciences, Guru Ghasidas University, Bilaspur, India
Abstract
In the present investigation, synthesis and anti-bacterial, analgesic and anthelmintic evaluation of a novel series of
fluoroquinolone derivatives clubbed with benzothiazole moeity has been described. The synthesized compounds
were characterised by spectral analysis (IR and 1H NMR). Preliminary results indicated that the most of the synthesized
compounds demonstrated good activities against gram negative and gram positive bacterial strains. Compounds
5a, 5b, 5f and 5k demonstrated potent anti-bacterial activities. Compound 5a exhibited most potent anti-bacterial
activity with MIC values of 04, 03, 08 and 15 µg/ mL against B. subtilis, S. aureus, E. coli and P. aeruginosa. Analogs 5a,
5c, 5g and 5h showed promising anthelmintic activity against Eisemia foetida in a low concentration as compared
to standard drug piperazine citrate with mean paralysis time ranging 22.60 2.46 to 31.60 3.07min. All synthesized
compounds depicted good in vivo analgesic activity with compound 5a exhibiting the most potent activity of 55.19%
inhibition of writhing in comparison to the standard drug.
Keywords: Fluoroquinolones, benzothiazoles, anti-bacterial, analgesic, anthelmintic
Introduction
of attraction of the scientists for long period. Several new
Fluoroquinolone anti-bacterial agents are among the
most attractive drugs in the field of anti-infective che-
motherapy1–3. e relevant breakthrough within this
class of agents occurred almost 20 years after the original
discovery when the addition of the fluorine molecule at
a position C-6 of the pharmacophore created the ‘fluoro-
quinolones’4. ese antibiotics exert their anti-microbial
activity by binding to two type II bacterial topoisomerase
enzymes, DNA gyrase (subunits encoded by gyrA and
gyrB) and topoisomerase IV (subunits encoded by gyrA
andgyrBforStaphylococcusaureus).isbindinginduces
permanent double stranded DNA breaks, and results in
cell death5,6. Ciprofloxacin is among one of the most suc-
cessful drugs of fluoroquinolone category7. e market
is heavily dominated by ciprofloxacin and levofloxacin,
which together command 65% ($3.3 billion) of global
sales8. Due to excellent pharmacokinetic and pharma-
cological profile, fluoroquinolones have been the centre
derivatives have been synthesized and evaluated for anti-
bacterial activity against many bacterial strains such as
P. aeruginosa, K. pneumoniae, S. pneumoniae, S. aureus,
S. epidermis etc.9–12 Fluoroquinolones analogs with anti-
tubercular13–14, anti-fungal15, anti-viral16 activities are well
known. Many research endeavours are being undertaken
to elaborate the possible role of fluoroquinolones in car-
cinogenesis and mutagenesis17–18
.
Heterocycles bearing nitrogen, sulphur and thiazole
moieties constitute the core for a number of biological
interesting compounds19–20. e 2-aminobenzothiazoles
scaffold is one of the privileged structures in medicinal
chemistry. Indeed various examples featuring this par-
ticular scaffold have been prepared, many exhibiting
remarkable biological activities. It has demonstrated a
myriad spectrum of biological activities such as anti-mi-
crobial21, anti-inflammatory, analgesic and anti-tumour
activity22.
Address for Correspondence: Dr. Prabodh Chander Sharma, Assistant Professor, Institute of Pharmaceutical Sciences, Kurukshetra
University, Kurukshetra 136119, India. Tel: +91-9416025460. E-mail: sharma_prabodh@rediffmail.com
(Received 02 July 2011; revised 22 July 2011; accepted 04 August 2011)
1

2
P. C. Sharma et al.
e prevalence of newly emerging virulence traits
in the presence of K2CO3 was refluxed at 80–85°C for 12 h.
Excess of solvent was removed in vacuo and the residue
was stirred with water (50 mL). e residue was washed
with 5% NaHCO3 and subsequently with water. e prod-
uct was dried and recrystallised from methanol.
and drug resistance of the pathogens towards antibiot-
ics have become a serious problem. us, the design of
newer agents active against the resistant micro-organ-
isms is of critical importance. Looking at the importance
of these heterocyclic nuclei, it is thought of interest to
accommodate 2-aminobenzothiazoles and fluoroquino-
lones in single molecular framework and screen them for
their various biological activities. Due to our continuous
interest23–26 and research program on design and syn-
thesis of novel anti-microbial agents a number of potent
fluoroquinolone derivatives27–29 have been synthesized.
Recently, we have reported synthesis of novel fluoro-
quinolone derivatives annulated with benzothiazoles
with promising anti-bacterial activity30. It was clearly
indicated that clubbing of fluoroquinolones with benzo-
thiazoles is worthwhile and the synthesized compounds
were of promising pharmacological significance. On the
basis of these facts, we are here reporting novel synthesis
and anti-bacterial, analgesic and anthelmintic activities
of substituted benzothiazole derivatives clubbed with
fluoroquinolones.
Procedure of synthesis of fluorquinolone derivatives
bearing acetamide linkage (5a-o)
A mixture of benzothiazole 3a-e (0.05 mmol), fluoroqui-
nolone 4a-e (0.05 mmol) and NaHCO3 (0.05 mmol) in
DMF (10 mL), was heated at 85–90°C. After consumption
of fluoroquinolone (monitored by TLC), H2O (20 mL),
was added and the precipitate was filtered and washed
with water to give product. Purification was achieved by
passage through silica gel column (chloroform-ethanol;
95:5). e product was crystallized from DMF-H2O to
give 5a-o. e novel derivatives were achieved through
the versatile and efficient synthetic route outlined in
Scheme 1 (Figure 1).
1-Cyclopropyl-6-fluoro-7-(4-(N-(6-chloro-1,3-ben-
zothiazol-2-yl)amino)-2-oxoethyl)piperazin-1-yl)-1,4-
dihydro-4-oxo-quinoline-3-carboxylic acid (5a). Yield
67%; m.p. 252–258°C; IR (cm−1): 3340 (NH str), 3076–2890
(C-H str), 1715 (C=O str), 1666 (CONH str), 1628 (C=O
Materials and methods
1
str), 1528 (C=C str), 1257 (C-O str), 1142 (C-N str); H
Chemistry
NMR (DMSO-d6) δ ppm: 1.34 (m, 4H, -CH2CH2- cyclo-
propyl), 3.28–3.84 (m, 9H, piperazine-H and cyclopro-
pyl-H), 4.16 (s, 2H, -CH2 methylene bridge), 4.84 (s, 1H,
-NH), 7.02–7.96 {m, 5H, aromatic (H5, H8-quinolone and
H4´, H5´, H7’-benzothiazole)}, 8.12 (s, 1H, H2-quinolone),
15.08 (s br, 1H, -COOH).
Chemicals and all solvents used in this study were
procured from Merck AG (Mumbai, India), SD Fines
(Mumbai, India), Sigma Aldrich (Bangalore, India) and
Qualigens (Navi Mumbai, India). Melting points were
determined on a Labindia MR-VIS visual melting range
apparatus (Mumbai, India) and are uncorrected. e
infrared (IR) spectra were recorded on a Perkin Elmer
(Waltham, MA), IR spectrophotometer (potassium bro-
mide disk). 1H NMR spectra were recorded using Bruker
400 (Fallanden, Switzerland) spectrometer and chemical
shifts are expressed as δ (ppm) with tetramethylsilane as
an internal standard.
1-Cyclopropyl-6-fluoro-7-(4-(N-(4,7-dichloro-1,3-
benzothiazol-2-yl)amino)-2-oxoethyl) piperazin-1-yl)-1-
,4-dihydro-4-oxo-quinoline-3-carboxylic acid (5b). Yield
66%; m.p. 241–244°C; IR (cm−1): 3320 (NH str), 3156–2877
(C-H str), 1705 (C=O str), 1674 (CONH str), 1628 (C=O
1
str), 1535 (C=C str), 1257 (C-O str), 1188 (C-N str); H
NMR (DMSO-d6) δ ppm: 1.25 (m, 4H, -CH2CH2- cyclo-
propyl), 3.36–3.93 (m, 9H, piperazine-H and cyclopro-
pyl-H), 4.32 (s, 2H, -CH2 methylene bridge), 5.00 (s, 1H,
-NH), 7.14–7.87 {m, 4H, aromatic (H5, H8- quinolone and
H5´, H6´- benzothiazole)}, 8.79 (s, 1H, H2-quinolone), 14.9
(s br, 1H, -COOH).
General procedure for synthesis
Procedure of synthesis of 2-amino-substituted
benzothiazoles (2a-g)
e requisite 2-aminobenzothiazoles 2a-g were prepared
by reaction of bromine (4mL, 0.05 mol) dissolved in
glacial acetic acid (37.5mL) which was added drop wise
with stirring to a solution of (0.05mol) of aniline 1a-g and
potassium thiocyanate (19.43g) dissolved in 90mL of 96%
glacial acetic acid while the temperature was kept below
35°C. After all the bromine solution has been added, the
mixture was stirred for ten hours and then filtered and the
residue was washed with water. e combined filtrate and
the washings were neutralized with ammonium hydrox-
ide. e precipitate was collected on filter and dried.
1-Cyclopropyl-6-fluoro-7-(4-(N-(6-nitro-1,3-benzo-
thiazol-2-yl)amino)-2-oxoethyl)
piperazin-1-yl)-1,4-
dihydro-4-oxo-quinoline-3-carboxylic acid (5c). Yield
68%; m.p. 262–265°C; IR (cm−1): 3360 (NH str), 3155–2839
(C-H str), 1720 (C=O str), 1674 (CONH str), 1630 (C=O
str), 1528 (C=C str), 1252 (C-N str), 1166(C-N str); 1H NMR
(DMSO-d6) δ ppm: 1.23 (m, 4H, -CH2CH2- cyclopropyl),
3.32–3.96 (m, 9H, piperazine-H and cyclopropyl-H), 4.12
(s, 2H, -CH2 methylene bridge), 4.76 (s, 1H, -NH), 7.21–
7.84 {m, 5H, aromatic (H5, H8- quinolone and H4´, H5´,
H7´- benzothiazole)}, 8.89 (s, 1H, H2-quinolone), 15.05 (s
br, 1H, -COOH).
Procedure of synthesis of 2-(2-chloroacetylamino)-substituted
benzothiazoles (3a-e)
Equimolar solution of benzothiazole (0.01 mmol) and
chloroacetyl chloride (0.01 mmol) in chloroform (30 mL)
1-Cyclopropyl-6-fluoro-7-(4-(N-(6-methyl-1,3-
benzothiazol-2-yl)amino)-2-oxoethyl) piperazin-1-yl)-
1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (5d).
Journal of Enzyme Inhibition and Medicinal Chemistry

Benzothiazole clubbed fluoroquinolone derivatives
3
Figure 1. Synthetic scheme for preparation of title compounds.
Yield 61%; m.p. 252–255°C; IR (cm−1): 3380 (NH str),
3183–2889(C-H str), 1713 (C=O str), 1674 (CONH str),
1628 (C=O str), 1551 (C=C str), 1227 (C-N str); H NMR
(DMSO-d6) δ ppm: 1.24 (m, 4H, -CH2CH2- cyclopropyl),
2.44 (m, 3H, -CH3 benzothiazole), 3.60–3.94 (m, 9H, pip-
erazine-H and cyclopropyl-H), 4.35 (s, 2H, -CH2 methyl-
ene bridge), 4.86 (s, 1H, -NH), 7.21–7.87 {m, 5H, aromatic
(H5, H8- quinolone and H4´, H5´, H7´- benzothiazole)}, 8.26
(s, 1H, H2-quinolone), 15.04 (s br, 1H, -COOH).
H7´- benzothiazole)}, 8.05 (s, 1H, H2-quinolone), 15.10 (s
br, 1H, -COOH).
1
1-Ethyl-6-fluoro-7-(4-(N-(6-chloro-1,3-benzothiazol-
2-yl)amino)-2-oxoethyl) piperazin-1-yl)-1,4-dihydro-4-
-oxo-quinoline-3-carboxylic acid (5f). Yield 58%; m.p.
232–235°C; IR (cm−1): 3350 (NH str), 3056–2833 (C-H
str), 1721 (C=O str), 1674 (CONH str), 1628 (C=O str),
1
1551 (C=C str), 1257 (C-N str), 1111 (C-N str); H NMR
(DMSO-d6) δ ppm: 1.35 (t, 3H, -CH3 ethyl), 2.24–2.36 (m,
2H, -CH2 ethyl), 3.34 (m, 8H, piperazine-H), 4.02 (s, 2H,
-CH2 methylene bridge), 4.85 (s, 1H, -NH), 6.98–7.86 {m,
5H, aromatic (H5, H8- quinolone and H4´, H5´, H7´- ben-
zothiazole)}, 8.56 (s, 1H, H2-quinolone), 14.94 (s br, 1H,
-COOH).
1-Cyclopropyl-6-fluoro-7-(4-(N-(6-fluoro-1,3-ben-
zothiazol-2-yl)amino)-2-oxoethyl)
piperazin-1-yl)-1-
,4-dihydro-4-oxo-quinoline-3-carboxylic acid (5e).
Yield 70%; m.p. 265–268°C; IR (cm−1): 3360 (NH str),
3068–2876 (C-H str), 1710 (C=O str), 1666 (CONH str),
1
1635 (C=O str), 1535 (C=C str), 1150 (C-N str); H NMR
1-Ethyl-6-fluoro-7-(4-(N-(4,7-dichloro-1,3-benzo-
(DMSO-d6) δ ppm: 1.14 (m, 4H, -CH2CH2- cyclopropyl),
3.46–3.74 (m, 9H, piperazine-H and cyclopropyl-H), 4.24
(s, 2H, -CH2 methylene bridge), 4.82 (s, 1H, -NH), 6.95–
7.72 {m, 5H, aromatic (H5, H8- quinolone and H4´, H5´,
thiazol-2-yl)amino)-2-oxoethyl)
piperazin-1-yl)-1,4-
dihydro-4-oxo-quinoline-3-carboxylic acid (5g). Yield
54%; m.p. 212–215°C; IR (cm−1): 3350 (NH str), 3056–2833
(C-H str), 1713 (C=O str), 1688 (CONH str), 1621 (C=O
© 2013 Informa UK, Ltd.

4
P. C. Sharma et al.
str), 1551 (C=C str), 1257 (C-N str), 1112 (C-N str); 1H NMR
(DMSO-d6) δ ppm: 1.35 (t, 3H, -CH3 ethyl), 2.24–2.36 (m,
2H, -CH2 ethyl), 2.98–3.31 (m, 8H, piperazine-H), 4.31 (s,
2H, -CH2 methylene bridge), 5.10 (s, 1H, -NH), 7.12–7.86
{m, 4H, aromatic (H5, H8- quinolone and H5´, H6´- ben-
zothiazole)}, 8.92 (s, 1H, H2-quinolone), 14.94 (s br, 1H,
-COOH).
piperazin-1-yl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic
acid (5l). Yield 59%; m.p. 244–247°C; IR (cm−1): 3350 (NH
str), 3086–2854 (C-H str), 1713 (C=O str), 1666 (CONH str),
1620 (C=O str), 1528 (C=C str), 1273 (C-N str), 1161 (C-N
1
str); H NMR (DMSO-d6) δ ppm: 1.21 (m, 4H, -CH2CH2-
cyclopropyl), 2.19–2.94 (m, 3H, -CH3 piperazine) 3.31–3.72
(m, 8H, piperazine-H and cyclopropyl-H), 3.78 (s, 3H,
OCH3), 4.08 (s, 2H, -CH2 methylene bridge), 4.89 (s, 1H,
-NH), 7.18–7.87 {m, 3H, aromatic (H5, quinolone and H5´,
H6´- benzothiazole)}, 9.04 (s, 1H, H2-quinolone), 14.09 (s br,
1H, -COOH).
1-Ethyl-6-fluoro-7-(4-(N-(6-nitro-1,3-benzothiazol-
2-yl)amino)-2-oxoethyl) piperazin-1-yl)-1,4-dihydro-4-
-oxo-quinoline-3-carboxylic acid (5h). Yield 57%; m.p.
222–225°C; IR (cm−1): 3350 (NH str), 3056–2833 (C-H
str), 1721 (C=O str), 1674 (CONH str), 1628 (C=O str),
1-Cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl-4-
(N-(6-nitro-1,3-benzothiazol-2-yl)amino)-2-oxoethyl)
piperazin-1-yl)-1,4-dihydro-4-oxo-quinoline-3-car-
boxylic acid (5m). Yield 57%; m.p. 182–185°C; IR (cm−1):
3310 (NH str), 3086–2839 (C-H str), 1720 (C=O str),
1670 (CONH str), 1628 (C=O str), 1551 (C=C str), 1257
1
1551 (C=C str), 1257 (C-N str), 1162 (C-N str); H NMR
(DMSO-d6) δ ppm: 1.38 (t, 3H, -CH3 ethyl), 2.28 (m, 2H,
-CH2 ethyl), 3.16–3.72 (m, 8H, piperazine-H), 4.26 (s, 2H,
-CH2 methylene bridge), 4.87 (s, 1H, -NH), 6.98–7.94 {m,
5H, aromatic (H5, H8- quinolone and H4´, H5´, H7´- ben-
zothiazole)}, 8.24 (s, 1H, H2-quinolone), 15.03 (s br, 1H,
-COOH).
1
(C-N str), 1154 (C-N str); H NMR (DMSO-d6) δ ppm:
1.12 (m, 4H, -CH2CH2- cyclopropyl), 2.46–2.76 (m, 3H,
-CH3 piperazine), 3.36–3.86 (m, 8H, piperazine-H and
cyclopropyl-H), 3.72 (s, 3H, OCH3), 4.24 (s, 2H, -CH2
methylene bridge), 4.89 (s, 1H, -NH), 7.10–7.96 {m,
3H, aromatic (H5, quinolone and H4´, H5´, H7´- benzo-
thiazole)}, 8.76 (s, 1H, H2-quinolone), 14.9 (s br, 1H,
-COOH).
1-Ethyl-6-fluoro-7-(4-(N-(6-methyl-1,3-benzothiaz-
ol-2-yl)amino)-2-oxoethyl) piperazin-1-yl)-1,4-dihydro-
4-oxo-quinoline-3-carboxylic acid (5i). Yield 52%; m.p.
196–199°C; IR (cm−1): 3350 (NH str), 3086–2834 (C-H
str), 1713 (C=O str), 1674 (CONH str), 1620 (C=O str),
1
1535 (C=C str), 1257 (C-N str), 1179 (C-N str); H NMR
(DMSO-d6) δ ppm: 1.36 (t, 3H, -CH3 ethyl), 2.24–2.34 (m,
2H, -CH2 ethyl), 2.48 (m, 3H, -CH3 benzothiazole) 3.12–
2.37 (m, 8H, piperazine-H), 4.10 (s, 2H, -CH2 methylene
bridge), 4.87 (s, 1H, -NH), 6.87–7.86 {m, 5H, aromatic (H5,
H8- quinolone and H4´, H5´, H7´- benzothiazole)}, 8.32 (s,
1H, H2-quinolone), 15.04 (s br, 1H, -COOH).
1-Cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl-4-
(N-(6-methyl-1,3-benzothiazol-2-yl)amino)-2-oxoethyl)
piperazin-1-yl)-1,4-dihydro-4-oxo-quinoline-3-car-
boxylic acid (5n). Yield 53%; m.p. 203–206°C; IR (cm−1):
3370 (NH str), 3056–2827 (C-H str), 1713 (C=O str), 1672
(CONH str), 1620 (C=O str), 1557 (C=C str), 1258 (C-N
1
1-Ethyl-6-fluoro-7-(4-(N-(6-fluoro-1,3-benzothiazol-
2-yl)amino)-2-oxoethyl) piperazin-1-yl)-1,4-dihydro-4-
-oxo-quinoline-3-carboxylic acid (5j). Yield 53%; m.p.
206–209°C; IR (cm−1): 3350 (NH str), 3156–2839 (C-H
str), 1720 (C=O str), 1674 (CONH str), 1620 (C=O str),
str), 1166 (C-N str); H NMR (DMSO-d6) δ ppm: 1.0 (m,
4H, -CH2CH2- cyclopropyl), 2.42–2.69 (m, 3H, -CH3 pip-
erazine), 2.48 (m, 3H, -CH3 benzothiazole), 3.46–3.84
(m, 8H, piperazine-H and cyclopropyl-H), 3.72 (s, 3H,
OCH3), 4.16 (s, 2H, -CH2 methylene bridge), 4.97 (s, 1H,
-NH), 7.24–7.93 {m, 4H, aromatic (H5, quinolone and H4´,
H5´, H7´- benzothiazole)}, 8.27 (s, 1H, H2-quinolone), 14.9
(s br, 1H, -COOH).
1-Cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl-4-
(N-(6-fluoro-1,3-benzothiazol-2-yl)amino)-2-oxoethyl)
piperazin-1-yl)-1,4-dihydro-4-oxo-quinoline-3-car-
boxylic acid (5o). Yield 56%; m.p. 226–229°C; IR (cm−1):
3380 (NH str), 3155–2839 (C-H str), 1720 (C=O str), 1674
(CONH str), 1620 (C=O str), 1551 (C=C str), 1258 (C-N
str), 1131 (C-N str); 1H NMR (DMSO-d6) δ ppm: 1.12 (m,
4H, -CH2CH2- cyclopropyl), 2.92 (m, 3H, -CH3 piperazine)
3.74 (m, 8H, piperazine-H and cyclopropyl-H), 3.78 (s,
3H, OCH3), 4.04 (s, 2H, -CH2 methylene bridge), 5.13 (s,
1H, -NH), 7.24–7.83 {m, 4H, aromatic (H5, quinolone and
H4´, H5´, H7´- benzothiazole)}, 9.04 (s, 1H, H2-quinolone),
15.04 (s br, 1H, -COOH).
1
1535 (C=C str), 1257 (C-N str), 1165 (C-N str); H NMR
(DMSO-d6) δ ppm: 1.26 (t, 3H, -CH3 ethyl), 1.96 (m, 2H,
-CH2 ethyl), 2.94–3.89 (m, 8H, piperazine-H), 4.14 (s, 2H,
-CH2 methylene bridge), 4.84 (s, 1H, -NH), 7.09–8.25 {m,
5H, aromatic (H5, H8- quinolone and H4´, H5´, H7´- ben-
zothiazole)}, 8.24 (s, 1H, H2-quinolone), 13.87 (s br, 1H,
-COOH).
1-Cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl-4-
(N-(6-chloro-1,3-benzothiazol-2-yl)amino)-2-oxoethyl)
piperazin-1-yl)-1,4-dihydro-4-oxo-quinoline-3-car-
boxylic acid (5k). Yield 64%; m.p. 183–186°C; IR (cm−1):
3340 (NH str), 3052–2854 (C-H str), 1710 (C=O str), 1674
(CONH str), 1628 (C=O str), 1551 (C=C str), 1257 (C-N
str), 1174 (C-N str); 1H NMR (DMSO-d6) δ ppm: 1.24 (m,
4H, -CH2CH2- cyclopropyl), 2.19–2.94 (m, 3H, -CH3 pip-
erazine) 3.33–3.74 (m, 8H, piperazine-H and cyclopro-
pyl-H), 3.75 (s, 3H, OCH3), 4.16 (s, 2H, -CH2 methylenee
bridge), 4.86 (s, 1H, -NH), 6.96–7.86 {m, 4H, aromatic (H5,
quinolone and H4´, H5´, H7´- benzothiazole)}, 8.69 (s, 1H,
H2-quinolone), 15.13 (s, 1H, -COOH).
Pharmacological screening
Anti-bacterial activity
1-Cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl-4-(N-
(4,7-dichloro-1,3-benzothiazol-2-yl)amino)-2-oxoethyl)
e anti-bacterial activity was determined against
two gram negative bacteria i.e., E. coli (NCDC 134), P.
Journal of Enzyme Inhibition and Medicinal Chemistry

Benzothiazole clubbed fluoroquinolone derivatives
5
aeroginosa (NCDC105) and three gram positive strains
i.e., B. subtilis (NCDC 71), B. polymoxa (NCDC 64) and
S. aureus (NCDC 110). e synthesized compounds were
screened for anti-bacterial activity by minimum inhibi-
tory concentration method31. Revival of these strains
was done as per protocol provided by NDRI, Karnal. e
bacterial cultures were stored at 4°C and culture was
maintained on nutrient agar plate. MIC values of the syn-
thesized compounds determined against various strains
are reported in Table 1.
Calculation of log P
To investigate the activity of the synthesized compounds
against gram negative and gram positive bacteria, the
quantitative effects of lipophillicity on anti-bacterial
activity were also studied. Partition coefficient, log P is
an important parameter for anti-bacterial activity, usu-
ally related to its pharmacological activity. Log P is a
measure of hydrophobicity, which is not only important
for the penetration and distribution of a drug but also for
the interaction of the drug with the receptor. Log P was
Table 1. Minimum inhibitory concentration (MIC) in µg/mL against B. polymyxa, B. subtilis, E. coli, P. aeruginosa,
S. aureus bacterial strains.
Gram (+)
Gram (−)
P. aeruginosa
Compounds
B. subtilis (NCDC 71)
B. polymyxa (NCDC 64)
S. aureus (NCDC 110)
E. coli (NCDC 134)
(NCDC 105)
5a
04
10
25
35
40
02
20
15
30
65
75
25
40
120
70
20
05
80
15
30
55
110
125
25
15
75
45
55
25
25
45
60
25
10
25
10
03
05
50
40
35
15
40
105
25
45
04
10
60
70
15
50
10
05
08
06
15
65
45
45
60
10
30
55
20
40
20
30
75
85
50
50
15
40
5b
5c
35
5d
20
5e
80
5f
50
5g
60
5h
125
65
5i
5j
35
5k
60
5l
70
5m
65
5n
75
5o
140
25
Ciprofloxacin
Norfloxacin
Gatifloxacin
40
100
Figure 2. e possible protonation states of fluoroquinolones.35
© 2013 Informa UK, Ltd.

6
P. C. Sharma et al.
calculated online by molinspiration software from the
Website (http://www.molinspiration.com/cgi-bin/prop-
erties). e value of log P was used as such given by the
software in the biological study.
outer membrane, and so lack the outer membrane pro-
tein and lipopolysaccharide. Hence the accumulation of
the drugs in gram positive bacteria takes place thorough
simple diffusion across the cytoplasmic membrane and
not affected by increasing the bulkiness of the N-7 substi-
tution34. e value of log MIC, molecular mass and cor-
relation coefficient (r) have been summarised in Tables
2 and 3. Correlation coefficient was calculated by the
formula as given below:
Correlation between partition coefficient log P and log
MIC
To determine the relationship between the calculated log
P and log MIC value, a simple regression was performed.
e partition of quinolones was generally consistent with
theknowledgethattheneutralspeciesoflikecompoundsis
more lipophilic than the zwitterions species (Figure 2). e
ratio of the zwitter ions to neutral species is very important
feature to describe the lipophilicity of fluoroquinolones32.
e following regression equation was, therefore, applied.
e value of log MIC, log P and correlation coefficient (r)
have been summarised in Tables 2 and 3.
N
XY −
X
Y
∑
∑
∑
r =
2
2
2
2
N
X
− ( X )
N Y − ( Y)
∑ ∑
∑
∑
where r is correlation coefficient, X series are Log P and
molecular mass, and Y series are Log MIC.
Anthelmintic activity
In the present work, anthelmintic activity of newly synthe-
sized compounds was evaluated using a variety of earth-
worms. Earthworms (Pheritima posthuma) were procured
from Department of Agriculture, Gurukul, Kurukshetra.
Suspension of the samples were prepared by triturating
the samples with 0.5% tween 80 and distilled water. e
resulting mixtures were then stirred using a mechanical
stirrer for 30min. e resulting suspensions were diluted
to contain 200mg in 5mL of test samples. ese suspen-
sions were used for anthelmintic studies. e standard
drug piperazine citrate was also used in the form of the
suspension with the same concentration in the same way.
2
Y =alog X +blog X +c
where Y=log MIC; X=log P; and a, b and c are constants.
Correlation between molecular mass and log MIC
e molecular mass and bulkiness at the substituent of
the substitution at C-7 position hinder penetration of qui-
nolones into gram positive bacteria through the porine
channel, although hydrophobic molecules appear to
enter via lipopolysaccharide or across the lipid bilayer33.
Conversely, gram positive bacteria do not possess an
Table 2. Log P, molecular mass and log MIC of the compounds 5a-o.
Correlation parameters
Log MIC
Compounds
Log P
2.27
2.88
1.55
2.04
1.76
2.28
2.89
1.56
2.05
1.77
2.59
3.19
1.87
2.36
2.07
Mol. Mass
556.00
590.41
566.52
535.51
539.53
543.94
578.43
554.55
523.64
527.51
600.02
634.52
610.63
579.65
583.61
B. subtilis
0.60
1.00
1.39
1.54
1.60
0.30
1.30
1.17
1.47
1.81
1.87
1.39
1.60
2.07
1.84
B. polymyxa
1.76
S. aureus
0.47
0.69
1.69
1.60
1.54
1.17
1.06
2.02
1.39
1.65
0.60
1.00
1.77
1.84
1.17
E. coli
0.90
0.77
1.54
1.30
1.90
1.69
1.77
2.09
1.81
1.54
1.77
1.84
1.84
1.87
2.14
P. aeruginosa
1.17
5a
5b
5c
5d
5e
5f
1.47
1.81
1.74
1.65
2.04
1.65
2.09
1.77
1.39
1.00
5g
5h
5i
1.76
1.47
1.87
1.74
1.65
1.30
5j
1.74
1.60
5k
5l
1.39
1.30
1.39
1.47
5m
5n
5o
1.65
1.87
1.77
1.92
1.39
1.69
Table 3. Correlation coefficient (r) between log MIC of tested strains and log P and molecular mass of compounds 5a-o.
Correlation coefficient (r)
Bacterial strains
B. subtilis
Log P
0.72
0.52
0.79
0.58
0.62
Molecular mass
0.32
0.26
0.47
0.36
0.29
B. polymoxa
S. aureus
E. coli
P. aeruginosa
Journal of Enzyme Inhibition and Medicinal Chemistry

Benzothiazole clubbed fluoroquinolone derivatives
7
Five earthworms of a variety and similar size were
placed in a petri dish of 4 inches diameter containing
50 mL suspension of the standard drug (piperazine
citrate) at room temperature. Another set of earth-
worms was kept as control in 50 mL suspension of
distilled water and 0.5% tween 80. en, 50 mL each of
the suspension of test samples were added into sepa-
rate petri dish containing five earthworms in each. e
time required for paralysis and death were recorded.
e death time was ascertained by placing the para-
lysed worm warm water at 50°C, which stimulated the
movement if the worm was alive. e mean paralysing
time and mean death time was calculated36. e process
was repeated with different varieties of earthworms.
Results of anthelmintic activity have been summarized
in Table 4.
e analgesic activity was measured against chemical
stimulus. For analgesic activity, the animals were divided
into groups consisting of six mice each. e control group
received normal saline: Tween 80 (95:5). e standard
group received diclofenac sodium 50 mg/Kg body weight
and the test groups received the synthetic compounds
at a dose of 50 mg/Kg body weight. irty minutes later,
nociception was induced by an intraperitoneal (IP)
injection of acetic acid (1.0%), 0.1 mL/10 g37. e number
of stretching or writhing was recorded from 5 to 15 min.
Results have been summarized in Table 5.
e percentage protection was calculated by the fol-
lowing formula:
% Protection =100 −(No. of writhes in test/
No. of writhes in control)×100
Analgesic activity
Results and discussion
Swissalbinomiceofeithersexweighing25–30 gwerepro-
cured from diseases free animal house CCS, Agricultural
University, Hisar, Haryana, India. e animals were
housed in animal house of Institute of Pharmaceutical
Sciences, Kurukshetra University, Kurukshetra, in poly-
carbonate cages in a room maintained under controlled
room temperature 22 2°C, relative humidity 60–70%,
and provided with food and water ad libitum. All the
experimental procedures and protocols used in the
study were reviewed by the Institutional Animal Ethics
Committee (Registration No 563/02/a/CPCSEA) and
were in accordance with the guidelines of the CPCSEA,
Ministry of Forests and Environment, Government
of India. e animals were deprived of food for 24 h
before experimentation but allowed free access to water
throughout.
Synthetic chemistry
e synthesis of various novel fluoroquinolone deriva-
tives was achieved in a 3-step procedure employing
various substituted anilines 1a-g as starting material.
Compound 2a-g were synthesized from substituted
anilines 1a-g, in the presence of potassium thiocynate
(ambidient nucleophile) from 1-phenyl urea in acidic
medium. is substituted 1-phenyl thiourea in pres-
ence of oxidising agent i.e., bromine was cyclised into
substituted 2-amino benzothiazoles. Compound 2a-g
on condensation with chloroacetyl chloride in the pres-
ence of K2CO3 as base and chloroform as solvent gave
2-(2-chloroacetyl amino)-substituted benzothiazoles 3a-
e. Compounds 3a-e were reacted with fluoroquinolones
4a-c in the presence of sodium bicarbonate as base and
Table 4. Anthelmintic activity of synthesized derivatives.
Concentration of compounds
Mean paralysing
Compounds
(mg/100mL)
time (min.) + SE.
26.00 2.00*
32.60 1.07
22.80 1.86**
23.20 1.28**
27.80 0.66
23.60 0.67**
26.80 1.49*
27.00 1.41
28.40 1.16
23.60 1.80**
24.60 1.63
29.00 2.70
25.60 1.20**
32.40 1.96
23.60 1.20**
–
Mean death time (min) + SE.
38.40 0.92**
43.20 1.24
38.20 0.58**
44.40 1.20
44.40 1.28
39.20 1.15**
43.20 2.08
40.40 1.03*
47.80 1.49
42.00 1.00
43.60 1.90
44.80 1.39
38.40 0.67**
48.00 1.30
43.80 1.53
–
5a
200
5b
200
5c
200
5d
200
5e
200
5f
200
5g
200
5h
200
5i
200
5j
200
5k
200
5l
200
5m
200
5n
200
5o
200
Control
Standard
–
200
34.40 1.03
44.80 1.02
Statistical analysis: All the results were expressed as mean standard mean error (SEM). Statistical analysis was done by using one way
ANOVA followed by Dunnett’s ‘t’ test and critical range for significance difference between two group of observation was taken as
*p < 0.05, **p < 0.01 and ***p < 0.001, compared with control.
© 2013 Informa UK, Ltd.

8
P. C. Sharma et al.
Table 5. Analgesic activity of the title compounds by acetic acid-induced writhing method.
No. of writhes mean SEM
Compounds
Dose (mg/Kg)
(% inhibition)
13.80 0.80*
15.60 1.32
14.20 1.14*
16.20 0.86
17.00 0.23
15.20 1.20
17.40 1.66
17.80 2.87
17.80 2.47
18.60 1.63
19.20 1.65
14.80 0.73*
17.60 1.63
20.80 2.03
15.00 0.70*
30.80 0.37
10.40 0.24
(%) Inhibition
55.19
49.35
53.89
47.40
44.80
50.64
43.50
42.20
42.20
39.61
37.66
51.94
42.85
32.46
44.80
–
5a
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
Control
Standard
67.23
Statistical analysis: All the results were expressed as mean standard mean error (SEM). Statistical analysis was done by using one
way ANOVA followed by Dunnett’s ‘t’ test and critical range for significance difference between two group of observation was taken as
**p<0.01 and ***p<0.001, compared with control.
DMF was heated. e product was recrystallised from
DMF-water to give 5a-o.
Compounds 5a, 5b, 5k, 5f and 5l were found to depict
even better than standard antibiotics ciprofloxacin, nor-
floxacinandgatifloxacinagainstS.aureus.ecompounds
5a, 5f, 5k and 5l (MIC=15–25 µg/mL) showed even better
MIC values as compared to the standard antibiotics cip-
rofloxacin, norfloxacin and gatifloxacin (MIC=10, 20 and
10 µg/mL) when tested against B. polymyxa. Analogs 5a
and 5f (MIC=04 and 02 µg/mL) are even better than the
standard antibiotics ciprofloxacin, norfloxacin and gati-
floxacin (MIC=20, 05 and 80 µg/mL) against B. subtilis.
Compounds 5c, 5d and 5g (MIC=20–35 µg/mL) showed
comparable MIC against standard antibiotics ciprofloxa-
cin, norfloxacin and gatifloxacin (MIC=25, 40 and 100 µg/
mL) when evaluated against E. coli. Compounds 5a and
5f (MIC=15 and 10 µg/mL) showed even better MIC
against the standard antibiotics ciprofloxacin, norfloxacin
and gatifloxacin (MIC=50, 15 and 40 µg/mL) when tested
against P. aeruginosa. e results of MIC test against
gram-positive and Gram negative bacteria revealed that
ciprofloxacin derivatives were more potent than the nor-
floxacin and gatifloxacin derivatives. ese data confirm
that the effect of changes in side chain of 7-piperazinyl
ring mainly depends on the substitution at N-4 position,
linkage group and position of the substituted ring.
e correlation between calculated Log P and Log
MIC 5a-o in case of B. subtilis and S. aureus showed
strong positive correlation (r = 0.72 and 0.79). However,
such correlation could not be established in case of
B. polymyxa, E. coli, P. aeruginosa (r = 0.52, 0.58, 0.62,
respectively). ese correlation results revealed that
lipophilicity of the molecule and penetration into the
cell membrane is not the only factor which can affect
the activity. Indeed, other factors such as the affin-
ity of the compounds for their target DNA gyrase and
e synthesized compounds are characterised by IR
spectra of analog 5a-o displaying characteristic absorp-
tion in the region 1721–1705 cm−1 showing the presence
of C=O str. NMR spectral data of fluoroquinolone deriva-
tives 5a-o singlet at δ 4.32–4.12 (2H) ppm correspond-
ing to proton of methylene bridge, clearly indicating the
presence of acetamide linkage in them.
Pharmacological screening
Keeping in view the biological potential of fluoroquinolo-
nes, it was decided to perform biological evaluation of all
the newly synthesized fluoroquinolone derivatives 5a-o.
Hence, all the synthesized compounds were subjected to
anti-bacterial, analgesic and anthelmintic screening in
order to evaluate their pharmacological potential.
Anti-bacterial activity
e newly synthesized compounds were screened for
their in vitro anti-bacterial activity against bacterial
strains. Compounds 5a-o were evaluated for their anti-
bacterial activity by MIC method, against two gram
negative bacteria i.e., E. coli (NCDC 134), P. aeruginosa
(NCDC105) and three gram positive strains i.e., B. sub-
tilis (NCDC 71), B. polymyxa (NCDC 64) and S. aureus
(NCDC 110). e major findings indicated that most of
the compounds were more active against gram positive
rather than gram negative bacteria. Compounds with
chloro substituted benzothiazole substituted ring com-
pounds were observed to be more potent than bromo,
nitro, fluoro and alkyl substituted compounds. For exam-
ple, 5a, 5b, 5f, 5k, 5l showed potent activity against gram
negative and gram positive bacteria.
Journal of Enzyme Inhibition and Medicinal Chemistry

Benzothiazole clubbed fluoroquinolone derivatives
9
topoisomerase IV can affect their MIC. Furthermore,
the heterogeneous nature and difference in the steric
effect of the tested N-4-piperazinyl substituted may
play important roles in the accommodation of these
molecules on the active sites of the enzyme. e cor-
relation between the molecular mass and Log MIC for
tested compounds 5a-o results in a weaker correlation
(r = 0.32, 0.26, 0.47, 0.36 and 0.29) for B. subtilis, B. poly-
myxa, S. aureus, E. coli and P. aeruginosa, respectively.
ese results indicate that the activity of compounds
not affected by increasing the bulkiness of the N-7 sub-
stituent’s in the present investigation.
norfloxacin and gatifloxacin. ey have also shown
promising anthelmintic activity and good in vivo analge-
sic activity. ese compounds may serve as useful lead
molecules for new antibiotic discoveries.
Acknowledgement
Prof. Om Prakash, Director, Institute of Pharmaceutical
Sciences and Lt. Gen. (Dr.) D.D.S. Sandhu, Vice
Chancellor, Kurukshetra University, India, are duly
acknowledged for providing necessary facilities.
Declaration of interest
Anthelmintic activity
e authors report no conflicts of interest. e authors
are alone responsible for the content and writing of the
paper.
e synthesized compounds were also evaluated for
the anthelmintic activity done against Eisemia foetida.
e results of this study revealed that all the com-
pounds exhibited promising anthelmintic activity at
low concentrations. Compound 5a, 5c, 5f, 5h and 5m
demonstrated potent activity with mean paralysis time
ranging from 22.60 2.46 to 31.60 3.07 min while most
of the compounds showed death time in the range of
42.00 1.00 min to 48.60 1.07 min. e standard drug
piperazine citrate at concentration of 200 mg/mL showed
activity with mean paralysis time 34.40 1.03 min and
mean death time 44.80 1.02 min. Results of anthel-
mintic activity showed that chloro and nitro substituted
compounds were more potent than other substitution at
benzothiazole ring. is showed that the increase elec-
tronegativity of the substituted group may increase the
activity of the compounds.
References
1. Sharma PC, Jain A, Jain S. Fluoroquinolone antibacterials: A
review on chemistry, microbiology and therapeutic prospects.
Acta Pol Pharm 2009;66:587–604.
2. Sharma PC, Saneja A, Jain S. Norfloxacin: A therapeutic review. Int
J Chem Sci 2008;6:1702–1713.
.
Sharma PC, Jain A, Jain S. erapeutic perspectives of
fluoroquinolones: An update. In proceedings of the 1st Rashtriya
Yuva Vagyanik Sammelan, Kurukshetra, November 28–30, 2008:
pp. 237–239.
4. Tillotson GS. Quinolones: Structure-activity relationships and
future predictions. J Med Microbiol 1996;44:320–324.
5. Sarkozy G. Quinolones: A class of anti-microbial agents. Vet Med
Czech 2001;46:257–274.
6. Drlica K. Mechanism of fluoroquinolone action. Curr Opin
Microbiol 1999;2:504–508.
Analgesic activity
7. Sharma PC, Jain A, Jain S, Pahwa R, Yar MS. Ciprofloxacin: Review
on developments in synthetic, analytical, and medicinal aspects. J
Enzyme Inhib Med Chem 2010;25:577–589.
8. Sharma PC, Alawadhi N, Sharma A, Pahwa R, Rajak H.
Fluoroquinolones in urinary tract infections: A study on perception
analysis of prescribers. Der Chem Sinica 2010;1:84–90.
9. Abuo-Rahma Gel-D, Sarhan HA, Gad GF. Design, synthesis,
antibacterial activity and physicochemical parameters of novel
N-4-piperazinyl derivatives of norfloxacin. Bioorg Med Chem
2009;17:3879–3886.
10. ForoumadiA,GhodsiS,EmamiS,NajjariS,SamadiN,FaramarziMA
et al. Synthesis and antibacterial activity of new fluoroquinolones
containing a substituted N-(phenethyl)piperazine moiety. Bioorg
Med Chem Lett 2006;16:3499–3503.
11. Asahina Y, Araya I, Iwase K, Iinuma F, Hosaka M, Ishizaki T.
Synthesis and antibacterial activity of the 4-quinolone-3-
carboxylic acid derivatives having a trifluoromethyl group as a
novel N-1 substituent. J Med Chem 2005;48:3443–3446.
12. Asahina Y, Iwase K, Iinuma F, Hosaka M, Ishizaki T.
Synthesis and antibacterial activity of 1-(2-fluorovinyl)-
All the derivatives were also screened for analgesic
activity by adopting standard protocol viz. acetic acid-
induced abdominal writhing test. Swiss albino mice
weighing 25–30 g were used for carrying the evaluation.
For abdominal writhing test, nociception was induced
by an intraperitoneal (IP) injection of acetic acid and
diclofenac sodium was used as a standard drug. e num-
ber of stretching or writhing were recorded for 5–15 min.
All the compounds exhibited significant analgesic activi-
ties. Among all, some compounds were observed to be
most active and depicted 47.40 and 55.19% inhibition of
writhing in comparison to the standard drug diclofenac
sodium (67.23%). From the results of analgesic activity, it
was clearly revealed that compounds with chloro substi-
tution at benzothiazole ring exhibit more potent activity
than other groups.
7-substituted-4-quinolone-3-carboxylic
acid
derivatives,
conformationally restricted analogues of fleroxacin. J Med Chem
2005;48:3194–3202.
13. Sriram D, Aubry A, Yogeeswari P, Fisher LM. Gatifloxacin
derivatives: Synthesis, antimycobacterial activities, and inhibition
of Mycobacterium tuberculosis DNA gyrase. Bioorg Med Chem
Lett 2006;16:2982–2985.
Conclusion
In this paper, we present a novel array of fluoroquino-
lone clubbed with benzothiazole derivatives which are
screened for anti-bacterial, anthelmintic and analgesic
activities. e experimental data reveal that the synthe-
sized compounds exhibit potent anti-bacterial activ-
ity as compared to the standard drugs ciprofloxacin,
14. Senthilkumar P, Dinakaran M, Yogeeswari P, Sriram D, China
A, Nagaraja V. Synthesis and antimycobacterial activities of
novel 6-nitroquinolone-3-carboxylic acids. Eur
2009;44:345–358.
J Med Chem
© 2013 Informa UK, Ltd.

10 P. C. Sharma et al.
15. Rameshkumar N, Ashokkumar M, Subramanian EH, Ilavarasan R,
Sridhar SK. Synthesis of 6-fluoro-1,4-dihydro-4-oxo-quinoline-3-
carboxylic acid derivatives as potential antimicrobial agents. Eur J
Med Chem 2003;38:1001–1004.
16. Hagihara M, Kashiwase H, Katsube T, Kimura T, Komai T,
Momota K et al. Synthesis and anti-HIV activity of arylpiperazinyl
fluoroquinolones: A new class of anti-HIV agents. Bioorg Med
Chem Lett 1999;9:3063–3068.
17. Azéma J, Guidetti B, Dewelle J, Le Calve B, Mijatovic T, Korolyov A
et al. 7-((4-Substituted)piperazin-1-yl) derivatives of ciprofloxacin:
Synthesis and in vitro biological evaluation as potential antitumor
agents. Bioorg Med Chem 2009;17:5396–5407.
18. Korolyov A, Dorbes S, Azéma J, Guidetti B, Danel M, Lamoral-eys
D et al. Novel lipophilic 7H-pyrido[1,2,3-de]-1,4-benzoxazine-
6-carboxylic acid derivatives as potential antitumor agents:
Improved synthesis and in vitro evaluation. Bioorg Med Chem
2010;18:8537–8548.
26. Kharb R, Shahar Yar M, Sharma PC. Recent advances and future
perspectives of triazole analogs as promising antiviral agents. Mini
Rev Med Chem 2011;11:84–96.
27. Sharma PC, Jain S. Synthesis and in-vitro antibacterial activity of some
novel N-nicotinoyl-1-ethyl-6-fluoro-1,4-dihydro-7-piperazin-1-yl-
4-oxoquinoline-3-carboxylates. Acta Pol Pharm 2008;65:551–556.
28. Sharma PC, Jain S. Synthesis and in vitro anti-bacterial activity
of certain novel N-nicotinoyl-1-ethyl-6-fluoro-1,4-dihydro-7-4-
subsituted piperazin-1-yl-4-oxoquinoline 3-carboxylates. Acta
Pharm Sciencia 2008;50:35–40.
29. Sharma OP, Sharma PC, Jain S. Synthesis and anti-bacterial
evaluation of fluoroquinolone derivatives In: Proceedings of
the International Conference on Bioscience, Biochemistry and
Bioinformatics, held at Singapore, February 26–28, 2011: pp. 1–5.
30. Sharma PC, Jain A, ShaharYar M, Pahwa R, Singh J, Goel S. Synthesis
and anti-bacterial evaluation of novel analogs of fluoroquinolones
annulated with 6-subsituted 2-aminobenzothiazoles. Arabian J
Chem 2011. Accepted manuscript doi: 10.1016/j.arabjc.2011.04.008.
31. Bauer AW, Kirby WM, Sherris JC, Turck M. Antibiotic susceptibility
testing by a standardized single disk method. Am J Clin Pathol
1966;45:493–496.
19. Sharma A, Kumar V, Jain S, Sharma PC. iazolidin-4-one and
hydrazone derivatives of capric acid as possible anti-inflammatory,
analgesic and hydrogen peroxide-scavenging agents. J Enzyme
Inhib Med Chem 2011;26:546–552.
20. Kumar V, Sharma A, Sharma PC. Synthesis of some novel 2,5-
disubstituted thiazolidinones from a long chain fatty acid as
possible anti-inflammatory, analgesic and hydrogen peroxide
scavenging agents. J Enzyme Inhib Med Chem 2011;26:198–203.
21. Huang S, Collony PJ. Synthesis of 2-N-alkyl (aryl) amino-7-
nitrobenzothiazoles. Tetrahedron Lett 2004;45:9373–9375.
22. Baell JB, Duggan PJ, Forsyth SA, Lewis RJ, Lok YP,
Schroeder CI. Synthesis and biological evaluation of nonpeptide
mimetics of omega-conotoxin GVIA. Bioorg Med Chem 2004;12:
4025–4037.
23. Kharb R, Yar MS, Sharma PC. New insights into chemistry and
anti-infective potential of triazole scaffold. Curr Med Chem
2011;18:3265–3297.
24. Sharma PC, Kaur G, Pahwa R, Sharma A, Rajak H. Quinazolines
analogs as potential therapeutic agents. Curr Med Chem 2011.
Accepted manuscript.
32. Ross DL, Riley CM. Physicochemical properties of fluoroquinolone
anti-microbials. Int J Pharm 1993;93:121–129.
33. Bazile S, Moreau N, Bouzard D, Essiz M. Relationships among
antibacterial activity, inhibition of DNA gyrase, and intracellular
accumulation of 11 fluoroquinolones. Antimicrob Agents
Chemother 1992;36:2622–2627.
34. PiddockLJ, JinYF, GriggsDJ. Effectofhydrophobicityandmolecular
mass on the accumulation of fluoroquinolones by Staphylococcus
aureus. J Antimicrob Chemother 2001;47:261–270.
35. Pistos C, Tsantili-Kakoulidou A, Koupparis M. Investigation of
the retention/pH profile of zwitterionic fluoroquinolones in
reversed-phase and ion-interaction high performance liquid
chromatography. J Pharm Biomed Anal 2005;39:438–443.
36. Dahiya R. Synthesis of a phenylalanine-rich peptide as potential
anthelmintic and cytotoxic agent. Acta Pol Pharm 2007;64:509–516.
37. Collier HO, Dinneen LC, Johnson CA, Schneider C. e abdominal
constriction response and its suppression by analgesic drugs in the
mouse. Br J Pharmacol Chemother 1968;32:295–310.
25. Kharb R, Sharma PC, Yar MS. Pharmacological significance of
triazole scaffold. J Enzyme Inhib Med Chem 2011;26:1–21.
Journal of Enzyme Inhibition and Medicinal Chemistry