Synthesis and in-vitro antibacterial activity of N-piperazinyl quinolone derivatives with a 2-thiernyl group

Article abstract of DOI:10.1211/146080800128736196

Novel N-substituted piperazinyl quinolones have been synthesized by reaction of piperazinyl quinolones with α-bromo-2-acetylthiophene or α-bromo-2-acetylthiophene oximes and evaluated for in-vitro antibacterial activity. Compounds with a [2-oxo-2-(2-thien

Full text of DOI:10.1211/146080800128736196

Pharm. Pharmacol. Commun. 2000, 6: 351±354
Received March 14, 2000
Accepted June 1, 2000
# 2000 Pharm. Pharmacol. Commun.
Synthesis and In-vitro Antibacterial Activity of N-Piperazinyl
Quinolone Derivatives with a 2-Thienyl Group
M. MIRZAEI AND A. FOROUMADI
The Research Centre of Kerman University of Medical Sciences, Kerman, Iran
Abstract
Novel N-substituted piperazinyl quinolones have been synthesized by reaction of piper-
azinyl quinolones with a-bromo-2-acetylthiophene or a-bromo-2-acetylthiophene oximes
and evaluated for in-vitro antibacterial activity.
Compounds with a [2-oxo-2-(2-thienyl)ethyl] group had antibacterial activity against
Gram-positive and Gram-negative bacteria similar to that of reference drugs, cipro¯oxacin,
nor¯oxacin and enoxacin. The oximes were almost as potent as the corresponding ketones
against staphylococci but less active against Gram-negative bacteria. Replacement of the
hydrogen of the oxime with a methyl group resulted in greater antibacterial activity against
both Gram-positive and Gram-negative bacteria, with minimum inhibitory concentrations
(MIC) ranging from 0Á0075 to 0Á5 mg mLÀ1; this potency was greater than that of the
reference compounds. The antibacterial activity of the O-benzyloxime derivatives was
lower. Cipro¯oxacin derivatives were usually more active than nor¯oxacin or enoxacin
derivatives.
Quinolones are structurally related to nalidixic
acid. New ¯uorinated piperazinyl quinolones,
congeners of nalidixic acid, have a much wider
in-vitro antibacterial spectrum and are more potent
than the parent compound (Mandell & Petri 1996).
During recent years much attention has been
devoted to the synthesis of new 4-quinolone-3-
carboxylates and to testing these newly prepared
agents for antibacterial activity (Foroumadi et al
1997). Further advances in quinolone development
are likely to provide better compounds for clinical
use (Androile 1999). Quinolones exert anti-
bactericidal activity primarily by inhibiting bac-
terial DNA gyrase. The inhibition of DNA gyrase
and the cell permeability of the quinolones are
greatly in¯uenced by the nature of the C-7 sub-
stituent on the standard structure of the 4-quino-
lone-3-carboxylic acids (Domagala et al 1986);
substitution at the C-7 position of the quinolone
molecule by bulky functional groups is also pos-
sible (Shen et al 1989). We have previously syn-
thesized and measured the in-vitro antibacterial
activity of N-[2-(2-furyl)-2-oxoethyl]piperazinyl
quinolones and related compounds; these com-
pounds had signi®cant antibacterial activity against
Gram-positive and Gram-negative bacteria (For-
oumadi et al 1999). We report here the synthesis
and in-vitro antibacterial activity of a series of
N-[2-oxo-2-(2-thienyl)ethyl and N-[2-oxyimino-2-
(2-thienyl)ethyl]piperazinyl quinolones (Figure 1
and Table 1, 6a±c and 8a±i).
Materials and Methods
Chemical procedures
a-Bromo-2-acetylthiophene (2) was prepared by
bromination of 2-acetylthiophene (1) (Mullen et al
1988). Reaction of the 2 with hydroxylamine
hydrochloride, O-methylhydroxylamine hydro-
chloride or O-benzylhydroxylamine hydrochloride
in methanol at room temperature (Schumann et al
1964; Schaefer & Mongold 1982) gave the inter-
mediate compounds 7a±c in good yields. Reaction
of quinolones (3, 4 or 5) with a-bromo-2-acetyl-
thiophene (2) or a-bromo-2-acetylthiophenoximes
(7a±c) without protection of the 3-carboxylic acid
group of the quinolones (Kondo et al 1986) in the
presence of sodium bicarbonate in dimethylforma-
mide (DMF) at room temperature afforded ketones
6a±c and oximes 8a±i respectively (Figure 1).
1
The compounds were characterized by H NMR
and IR spectroscopy and by microanalysis. The
Correspondence: A. Foroumadi, Department of Medicinal
Chemistry, Faculty of Pharmacy, Haft Bagh St, Kerman, Iran.

352
M. MIRZAEI AND A. FOROUMADI
Figure 1. Synthesis of N-substituted piperazinyl quinolones.
In-vitro antibacterial activity
purity of all the products was determined by thin-
layer chromatography with several mobile phases
of different polarity. The reaction times and phy-
sical properties of the products are listed in Table 1.
The in-vitro antibacterial activity of the test com-
pounds against Gram-positive (Staphylococcus
aureus and Staphylococcus epidermidis) and Gram-
Table 1. Physical properties of N-substituted piperazinyl quinolones.
Compound
Y
R
X
mp (ꢀC)
Yield (%)
Crystallization solvent
Reaction time (h)
6a
6b
6c
8a
8b
8c
8d
8e
8f
O
O
O
NOH
NOH
NOH
Cyclopropyl
Ethyl
Ethyl
Cyclopropyl
Ethyl
Ethyl
Cyclopropyl
Ethyl
Ethyl
Cyclopropyl
Ethyl
Ethyl
CH
CH
N
CH
CH
N
CH
CH
N
CH
CH
N
196±198
218±220
208±210
238±240
250±252
248±250
250±252
233±235
196±198
138±140
176±178
150±152
65
73
70
45
40
45
40
60
67
45
54
50
EtOH
EtOH
EtOH
48
48
48
72
48
60
168
48
168
96
96
168
CHCl3±EtOH
CHCl3±EtOH
CHCl3±EtOH
EtOH
NOCH3
NOCH3
NOCH3
NOCH2C6H5
NOCH2C6H5
NOCH2C6H5
EtOH
EtOH
EtOH
EtOH
EtOH
8g
8h
8i

ANTIBACTERIAL ACTIVITY OF 2-THIENYL N-PIPERAZINYL QUINOLONES
353
negative (Escherichia coli, Klebsiella pneumoniae,
Enterobacter cloacae) bacteria was tested by use of
conventional agar-dilution procedures (Baron &
Finegold 1990) and compared with that of cipro-
¯oxacin, nor¯oxacin and enoxacin.
Gram-positive and Gram-negative bacteria (For-
oumadi et al 1997, 1999).
In this study a series of N-[2-oxo-(2-thienyl)ethyl,
N-[2-hydroxyimino-2-(2-thienyl)ethyl], N-[2-meth-
oxyimino-2-(2-thienyl)ethyl] and N-[2-phenyl-
methoxyimino-2-(2-thienyl)ethyl]piperazinyl quino-
lones (6a±c and 8a±i) (Figure 1; Table 1) were
synthesized and evaluated for in-vitro antibacterial
activity.
The activity of compounds 6a±c and 8a±i was
tested against Gram-positive and Gram-negative
bacteria. The MIC was determined by use of con-
ventional agar-dilution procedures (Baron & Fine-
gold 1990). Cipro¯oxacin (3), nor¯oxacin (4) and
enoxacin (5) were chosen as standard controls.
Results obtained from testing of antibacterial
activity are summarized in Table 2.
Twofold serial dilutions of the compounds and
reference drugs were prepared in Muller-Hinton
agar. Drugs (6Á4 mg) were dissolved in dimethyl-
sulphoxide (DMSO; 1 mL) and the solution was
diluted with water (9 mL). Further progressive
double-dilutions with melted Muller-Hinton agar
were performed to obtain the required concentra-
tions of 64, 32, 16, 8, 4, 2, 1, 0Á5, 0Á25, 0Á13, 0Á06,
0Á03, 0Á015, 0Á0075 and 0Á00375 mg mLÀ1. Petri
dishes were inoculated with 1±5 6 104 colony-
forming units and incubated at 37ꢀC for 18 h. The
minimum inhibitory concentration (MIC) was the
lowest concentration of the test compound which
resulted in no visible growth on the plate. To ensure
that the solvent had no effect on bacterial growth, a
control test was performed with test medium sup-
plemented with DMSO at the same dilutions as
used in the experiment.
Compounds with
a
2-oxo-2-(2-thienyl)ethyl
group (6a±c) had antibacterial activity similar to
that of cipro¯oxacin, nor¯oxacin and enoxacin
against both Gram-positive and Gram-negative
bacteria. The oximes 8a±c were more potent than
the reference compounds against Gram-positive
bacteria although the potency against Gram-nega-
tive bacteria was signi®cantly less. These ®ndings
are similar to those of our previous study (For-
oumadi et al 1999).
Results and Discussion
The nature of the functional group at the 7 position
of the quinolone ring system is known to in¯uence
the range and extent of in-vitro antibacterial
activity. We have previously reported a series of
quinolones with N-(2-oxo-2-phenyl ethyl), N-[2-(2-
furyl)-2-oxoethyl]piperazinyl quinolones and rela-
ted compounds attached to the 7 position which
had signi®cant antibacterial activity against some
In contrast with our previous study, which
showed that replacing the hydrogen of the oxime
by a methyl group reduced in-vitro antibacterial
activity (Foroumadi et al 1999), in this study all
three compounds with methoxyimino substitution
(8d±f), were more active than cipro¯oxacin, nor-
¯oxacin and enoxacin against both Gram-positive
and Gram-negative bacteria. Replacement of the
Table 2. In-vitro antibacterial activity of piperazinyl quinolones expressed as the minimum inhibitory concentration (MIC).
MIC (mg mLÀ1
)
Compound
S. aureus
ATCC 6538p
S. epidermidis
ATCC 12228
E. coli
ATCC 8739
K. pneumoniae
ATCC 10031
E. cloacae
PTCC 1003
6a
6b
6c
8a
8b
8c
8d
8e
8f
8g
8h
8i
0Á5
0Á5
0Á5
0Á06
0Á5
0Á13
0Á5
0Á5
0Á5
0Á5
64
0Á25
0Á5
0Á0075
0Á06
0Á25
0Á5
0Á25
0Á25
0Á5
0Á06
1
0Á25
0Á5
0Á25
2
1
0Á25
0Á06
0Á06
0Á5
4
8
16
4
16
0Á03
0Á13
0Á25
8
> 64
> 64
0Á13
0Á13
0Á13
8
0Á0075
0Á06
0Á25
4
16
64
0Á06
0Á25
0Á13
0Á06
0Á25
0Á5
0Á5
0Á5
64
32
32
64
64
> 64
0Á06
0Á25
0Á5
Cipro¯oxacin (3)
Nor¯oxacin (4)
Enoxacin (5)
0Á25
0Á25
1
1
1
0Á5

354
M. MIRZAEI AND A. FOROUMADI
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