Synthesis and in vitro antibacterial activity of some N-(5-aryl-1,3,4-thiadiazole-2-yl)piperazinyl quinolone derivatives

Article abstract of DOI:10.1016/S0014-827X(03)00191-5

A series of N-[5-(1-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazole-2-yl] and N-[5-(nitrophenyl)-1,3,4-thiadiazole-2-yl] piperazinyl quinolone derivatives (5a-c and 5d-l) were synthesized and evaluated for in vitro antibacterial activity against some Gram-positive and Gram-negative bacteria. The antibacterial data revealed that all nitroimidazole derivatives (5a-c) showed interesting activity against tested Gram-positive bacteria (minimum inhibitory concentration, MIC=0.008-0.03 μg/ml) while they did not show good activity against Gram-negative organisms. Despite the significant activity of nitroimidazole series, all nitrophenyl analogues (5d-l) were inactive against both Gram-positive and Gram-negative bacteria. Among all of the tested compounds, 5a (ciprofloxacin derivative in nitroimidazole series) exhibited excellent activity against Staphylococcus aureus and Staphylococcus epidermidis (MIC=0.008 μg/ml).

Full text of DOI:10.1016/S0014-827X(03)00191-5

Il Farmaco 58 (2003) 1023Á1028
/
www.elsevier.com/locate/farmac
Synthesis and in vitro antibacterial activity of some N-(5-aryl-1,3,4-
thiadiazole-2-yl)piperazinyl quinolone derivatives
Alireza Foroumadi *, Fatemeh Soltani, Mohammad Hasan Moshafi,
Rogheeyeh Ashraf-Askari
Department of Medicinal Chemistry, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
Received 4 April 2003; accepted 15 July 2003
Abstract
A series of N-[5-(1-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazole-2-yl] and N-[5-(nitrophenyl)-1,3,4-thiadiazole-2-yl] piperazinyl
quinolone derivatives (5aÁ
and Gram-negative bacteria. The antibacterial data revealed that all nitroimidazole derivatives (5aÁ
against tested Gram-positive bacteria (minimum inhibitory concentration, MICꢀ0.008Á0.03 mg/ml) while they did not show good
activity against Gram-negative organisms. Despite the significant activity of nitroimidazole series, all nitrophenyl analogues (5dÁl)
/
c and 5dÁ/l) were synthesized and evaluated for in vitro antibacterial activity against some Gram-positive
/
c) showed interesting activity
/
/
/
were inactive against both Gram-positive and Gram-negative bacteria. Among all of the tested compounds, 5a (ciprofloxacin
derivative in nitroimidazole series) exhibited excellent activity against Staphylococcus aureus and Staphylococcus epidermidis
(MICꢀ0.008 mg/ml).
/
´
# 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: Antibacterial activity; N-Piperazinyl quinolones; Minimum inhibitory concentration
1. Introduction
yl]piperazinyl quinolones which had significant activity
against some Gram-positive bacteria [7].
Fluoroquinolones have a useful role in the treatment
of many bacterial infectious [1]. They exert their
antibacterial activity primarily by inhibiting bacterial
enzymes, DNA gyrase and topoisomerase IV [2].
In recent years much attention has been devoted to
the synthesis of new quinolones and to testing these
agents for antibacterial activity [3,4]. The rapid growth
in the quinolone research changed the whole face of the
previous SAR concepts. Structure modification at all
positions of the quinolone nucleus, except the 4-oxo
group, have successfully led to the discovery of potent
antimicrobial agents [5]. In addition, a position on the
quinolone molecule, where substitutions of bulky func-
tional groups are permitted, is at C-7 [6].
Considering the fact that 2,5-disubstituted-1,3,4-thia-
diazole derivatives [8,9] and 5-nitro-2-imidazolyl analo-
gues (e.g. metronidazole) [10,11] have antibacterial
activity, a new series of N-substituted piperazinyl
quinolones carrying a 5-(1-methyl-5-nitro-2-imidazo-
lyl)-1,3,4-thiadiazole moiety (5aÁc) were designed and
/
synthesized as potential antibacterial agents. Also, as a
continuation of this research, we have synthesized and
evaluated some N-[5-(nitrophenyl)-1,3,4-thiadiazol-2-
yl]piperazinyl quinolones (5dÁl) for their antibacterial
/
activity.
2. Experimental
Recently, we reported the synthesis and antibacterial
activity of N-[5-(5-nitro-2-furyl)-1,3,4-thiadiazole-2-
2.1. Chemistry
Melting points were taken on Electrothermal IA-9100
Capillary apparatus and are uncorrected. The IR
spectra were obtain on Shimadzu 470 spectropho-
* Corresponding author.
E-mail address: aforoumadi@yahoo.com (A. Foroumadi).
1
tometer (potassium bromide disks). H NMR spectrum
´
0014-827X/03/$ - see front matter # 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
doi:10.1016/S0014-827X(03)00191-5

1024
A. Foroumadi et al. / Il Farmaco 58 (2003) 1023Á1028
/
was recorded on a Bruker DRX-500 Avance instrument.
Chemical shifts are reported in parts per million (d)
relative to tetramethyl silane as an internal standard.
Hz), 8.24 (s, 1H, H4-imidazole), 4.55 (q, 2H, CH2, Jꢀ
7.1 Hz), 4.35 (s, 3H, CH3), 4.07Á4.05 (m, 4H, CH2,
piperazine), 3.85Á3.83 (m, 4H, CH2, piperazine), 1.43
ppm (t, 3H, CH3, Jꢀ7.1 Hz).
/
/
/
/
2.2. Synthesis of compounds 5aÁl
/
2.2.4. 1-Cyclopropyl-6-fluoro-7-{4-[5-(2-nitrophenyl)-
1,3,4-thiadiazole-2-yl]-1-piperazinyl}-4-oxo-1,4-dihydro-
3-quinoline carboxylic acid (5d)
This compound was prepared as described for 5a in
69% yield. Reaction time: 8 h, temperature: 120 8C, m.p.
2.2.1. 1-Cyclopropyl-6-fluoro-7-{4-[5-(1-methyl-5-nitro-
2-imidazolyl)-1,3,4-thiadiazole-2-yl]-1-piperazinyl}-4-
oxo-1,4-dihydro-3-quinoline carboxylic acid (5a)
A mixture of compound 3a (246 mg, 1 mmol),
ciprofloxacin (331 mg, 1 mmol) and sodium bicarbonate
(84 mg, 1 mmol) in dimethylformamide (DMF) (5 ml)
was heated under reflux at 90 8C for 6 h. The solvent
was removed under reduced pressure. Water was added
to the residue, the solids were filtered, washed with H2O
and crystallized from DMF giving 448 mg of 5a in 83%
289Á
(CÄ
O) and 1591, 1337/cm (NO2). 1H NMR (DMSO-d6,
500 MHz) d: 8.68 (s, 1H, H2-quinoline), 8.01 (d, 1H,
phenyl, Jꢀ8 Hz) 7.96 (d, 1H, H5-quinoline, Jꢀ13.0
Hz), 7.85Á7.79 (m, 2H, phenyl), 7.78Á7.74 (m, 1H,
phenyl), 7.65 (d, 1H, H8-quinoline, Jꢀ7.2 Hz), 3.87Á
3.78 (m, 5H, 4H, piperazine and 1H, CH), 3.57Á3.53 (m,
4H, piperazine), 1.36Á1.20 ppm (m, 4H, cyclopropyl).
/
290 8C (dec.) (DMF). IR (KBr) nmax: 1728, 1628
/
/
/
/
/
/
/
yield, m.p. 307Á
(CÄ
O) and 1523, 1366/cm (NO2). 1H NMR (DMSO-d6,
500 MHz) d: 8.70 (s, 1H, H2-quinoline), 8.2 (s, 1H, H4-
imidazole), 7.97 (d, 1H, H5-quinoline, Jꢀ13 Hz), 7.66
(d, 1H, H8-quinoline, Jꢀ7 Hz), 4.35 (s, 3H, CH3),
3.88Á3.84 (m, 4H, piperazine), 3.60Á3.53 (m, 5H, 4H,
piperazine and 1H, CH), 1.34Á1.20 ppm (m, 4H,
cyclopropyl).
/
310 8C (dec.). IR (KBr) nmax: 1715, 1619
/
/
/
/
2.2.5. 1-Ethyl-6-fluoro-7-{4-[5-(2-nitrophenyl)-1,3,4-
thiadiazole-2-yl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-
quinoline carboxylic acid (5e)
This compound was prepared as described for 5b in
73% yield, reaction time: 12 h, temperature: 90 8C, m.p.
/
/
/
/
284Á
(CÄ
O) and 1532, 1352/cm (NO2). 1H NMR (DMSO-d6,
500 MHz) d: 8.98 (s, 1H, H2-quinoline), 8.03 (d, 1H,
phenyl, Jꢀ7.9 Hz), 7.99 (d, 1H, H5-quinoline, Jꢀ13.0
Hz), 7.84Á7.75 (m, 3H, phenyl), 7.29 (d, 1H, H8-
quinoline, Jꢀ7.0 Hz), 4.64Á4.60 (m, 2H, CH2), 3.80Á
3.76 (m, 4H, piperazine), 3.58Á3.53 (m, 4H, piperazine),
1.45 ppm (t, 3H, CH3, Jꢀ7.0 Hz).
/
286 8C (dec.) (DMF). IR (KBr) nmax: 1712, 1628
2.2.2. 1-Ethyl-6-fluoro-7-{4-[5-(1-methyl-5-nitro-2-
imidazolyl)-1,3,4-thiadiazole-2-yl]-1-piperazinyl}-4-oxo-
1,4-dihydro-3-quinoline carboxylic acid (5b)
A mixture of compound 3a (246 mg, 1 mmol),
norfloxacin (319 mg, 1 mmol) and sodium bicarbonate
(84 mg, 1 mmol) in DMF (5 ml) was heated under reflux
at 90 8C for 6 h. The solvent was removed under reduced
pressure. Water was added to the residue, the solids were
filtered, washed with H2O and crystallized from DMF
/
/
/
/
/
/
/
/
/
2.2.6. 1-Ethyl-6-fluoro-7-{4-[5-(2-nitrophenyl)-1,3,4-
thiadiazole-2-yl]-1-piperazinyl}-4-oxo-1,4-dihydro-1,8-
naphthyridine-3-carboxylic acid (5f)
This compound was prepared as described for 5c in
80% yield, reaction time: 12 h, temperature: 120 8C, m.p.
giving 370 mg of 5b in 70% yield, m.p. 302Á
/
304 8C
(dec.). IR (KBr) nmax: 1720, 1625 (CÄ
/
O) and 1520, 1330/
1
cm (NO2). H NMR (DMSO-d6, 500 MHz) d: 8.98 (s,
1H, H2-quinoline), 8.2 (s, 1H, H4-imidazole), 8.16 (d,
1H, H5-quinoline, Jꢀ
line, Jꢀ7 Hz), 4.64Á4.59 (m, 2H, CH2), 4.35 (s, 3H,
CH3), 3.85Á3.81 (m, 4H, piperazine), 3.61Á3.56 (m, 4H,
piperazine), 1.44 ppm (t, 3H, CH3, Jꢀ7 Hz).
/
13 Hz), 7.27 (d, 1H, H8-quino-
285Á
(CÄ
O), 1523, 1372/cm (NO2). 1H NMR (DMSO-d6, 500
MHz) d: 9.01 (s, 1H, H2-quinoline), 8.16 (d, 1H, H5-
quinoline, Jꢀ13.2 Hz), 8.02 (d, 1H, phenyl, Jꢀ7.9 Hz),
7.88Á7.84 (m, 1H, phenyl), 7.83Á7.81 (m, 2H, phenyl),
4.55 (q, 2H, CH2, Jꢀ7.0 Hz), 4.07Á4.05 (m, 4H,
piperazine), 3.79Á3.77 (m, 4H, piperazine), 1.42 ppm
(t, 3H, CH3, Jꢀ7.0 Hz).
/
287 8C (dec.) (DMF). IR (KBr) nmax: 1715, 1628
/
/
/
/
/
/
/
/
/
/
2.2.3. 1-Ethyl-6-fluoro-7-{4-[5-(1-methyl-5-nitro-2-
imidazolyl)-1,3,4-thiadiazole-2-yl]-1-piperazinyl}-4-oxo-
1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (5c)
A mixture of compound 3a (246 mg, 1 mmol),
enoxacin (320 mg, 1 mmol) and sodium bicarbonate
(84 mg, 1 mmol) in DMF (5 ml) was heated under reflux
at 90 8C for 6 h. The solvent was removed under reduced
pressure. Water was added to the residue, the solids were
filtered, washed with H2O and crystallized from DMF
/
/
/
/
2.2.7. 1-Cyclopropyl-6-fluoro-7-{4-[5-(3-nitrophenyl)-
1,3,4-thiadiazole-2-yl]-1-piperazinyl}-4-oxo-1,4-dihydro-
3-quinoline carboxylic acid (5g)
This compound was prepared as described for 5a in
69% yield, reaction time: 10 h, temperature: 120 8C, m.p.
giving 444 mg of 5c in 84% yield, m.p. 315Á
(dec.). IR (KBr) nmax: 1715, 1625 (CÄO) and 1523, 1363/
cm (NO2). H NMR (DMSO-d6, 500 MHz) d: 9.01 (s,
1H, H2-quinolone), 8.17 (d, 1H, H5-quinolone, Jꢀ13.3
/
316 8C
303Á
(CÄ
O) and 1523, 1372/cm (NO2). 1H NMR (DMSO-d6,
500 MHz) d: 8.70 (s, 1H, H2-quinoline), 8.58Á8.55 (m,
1H, phenyl), 8.33Á8.30 (m, 1H, phenyl), 8.25Á8.23 (m,
/
305 8C (dec.) (DMF). IR (KBr) nmax: 1712, 1628
/
/
1
/
/
/
/

A. Foroumadi et al. / Il Farmaco 58 (2003) 1023Á
/
1028
1025
1H, phenyl), 7.98 (d, 1H, H5-quinoline, Jꢀ
7.82 (t, 1H, phenyl, Jꢀ8.12 Hz), 7.66 (d, 1H, H8-
quinoline, Jꢀ7 Hz), 3.87Á3.81 (m, 5H, 4H, piperazine
and 1H, CH), 3.58Á3.53 (m, 4H, piperazine), 1.25Á1.15
ppm (m, 4H, cyclopropyl).
/
13.0 Hz),
7.82 (t, 1H, phenyl, Jꢀ
7.0 Hz), 4.07Á4.05 (m, 4H, piperazine), 3.84Á
4H, piperazine), 1.43 ppm (t, 3H, CH3, Jꢀ7.0 Hz).
/
8.0 Hz), 4.55 (q, 2H, CH2, Jꢀ
/
/
/
/3.82 (m,
/
/
/
/
/
2.2.10. 1-Cyclopropyl-6-fluoro-7-{4-[5-(4-nitrophenyl)-
1,3,4-thiadiazole-2-yl]-1-piperazinyl}-4-oxo-1,4-dihydro-
3-quinoline carboxylic acid (5j)
This compound was prepared as described for 5a in
86% yield, reaction time: 12 h, temperature: 110 8C, m.p.
2.2.8. 1-Ethyl-6-fluoro-7-{4-[5-(3-nitrophenyl)-1,3,4-
thiadiazole-2-yl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-
quinoline carboxylic acid (5h)
This compound was prepared as described for 5b in
82% yield, reaction time: 24 h, temperature: 90 8C, m.p.
335Á
(CÄ
O) and 1535, 1365/cm (NO2). 1H NMR (DMSO-d6,
500 MHz) d: 8.70 (s, 1H, H2-quinoline), 8.35 (d, 2H,
phenyl, Jꢀ8.5 Hz), 8.09 (d, 2H, phenyl, Jꢀ8.5 Hz),
7.98 (d, 1H, H5-quinoline, Jꢀ13.5 Hz), 7.66 (d, 1H,
H8-quinoline, Jꢀ7.0 Hz), 3.87Á3.84 (m, 4H, pipera-
zine), 3.59Á3.54 (m, 5H, 4H, piperazine and 1H, CH),
1.36Á1.20 ppm (m, 4H, cyclopropyl).
/
336 8C (dec.) (DMF). IR (KBr) nmax: 1720, 1625
/
307Á
(CÄ
O) and 1591, 1335/cm (NO2). 1H NMR (DMSO-d6,
500 MHz) d: 8.95 (s, 1H, H2-quinoline), 8.57Á8.55 (m,
1H, phenyl), 8.33Á8.30 (m, 1H, phenyl), 8.25Á8.22 (m,
1H, phenyl), 7.99 (d, 1H, H5-quinoline, Jꢀ12.8 Hz),
7.82 (t, 1H, phenyl, Jꢀ8 Hz), 7.28 (d, 1H, H8-
quinoline, Jꢀ7.1 Hz), 4.65Á4.55 (m, 2H, CH2), 3.85Á
3.80 (m, 4H, piperazine), 3. 57Á3.52 (m, 4H, piperazine),
1.44 ppm (t, 3H, CH3, Jꢀ6.9 Hz).
/
309 8C (dec.) (DMF). IR (KBr) nmax: 1728, 1620
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
2.2.11. 1-Ethyl-6-fluoro-7-{4-[5-(4-nitrophenyl)-1,3,4-
thiadiazole-2-yl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-
quinoline carboxylic acid (5k)
/
2.2.9. 1-Ethyl-6-fluoro-7-{4-[5-(3-nitrophenyl)-1,3,4-
thiadiazole-2-yl]-1-piperazinyl}-4-oxo-1,4-dihydro-1,8-
naphthyridine-3-carboxylic acid (5i)
This compound was prepared as described for 5c in
74% yield, reaction time: 8 h, temperature: 95 8C, m.p.
This compound was prepared as described for 5b in
93% yield, reaction time: 12 h, temperature: 120 8C, m.p.
(dec.) 345Á
(CÄ
O) and 1536, 1350/cm (NO2). 1H NMR (DMSO-d6,
500 MHz) d: 8.98 (s, 1H, H2-quinoline), 8.35 (d, 2H,
phenyl, Jꢀ8.86 Hz), 8.09 (d, 2H, phenyl, Jꢀ8.86 Hz),
7.99 (d, 1H, H5-quinoline, Jꢀ13.1 Hz), 7.29 (d, 1H,
H8-quinoline, Jꢀ6.9 Hz), 4.62 (q, 2H, CH2, Jꢀ7.0
Hz), 3.85Á4.82 (m, 4H, piperazine), 3.62Á3.58 (m, 4H,
piperazine), 1.45 ppm (t, 3H, CH3, Jꢀ7.0 Hz).
/
347 8C (DMF). IR (KBr) nmax: 1715, 1623
/
328Á
(CÄ
O) and 1536, 1365/cm (NO2). 1H NMR (DMSO-d6,
500 MHz) d: 9.01 (s, 1H, H2-quinoline), 8.58Á8.55 (m,
1H, phenyl), 8.33Á8.30 (m, 1H, phenyl), 8.25Á8.22 (m,
1H, phenyl), 8.17 (d, 1H, H5-quinoline, Jꢀ13.2 Hz),
/
330 8C (dec.) (DMF). IR (KBr) nmax: 1720, 1625
/
/
/
/
/
/
/
/
/
/
/
/
/
Scheme 1. Synthesis of some N-piperazinyl quinolones 5aÁl.
/

Table 1
In vitro antibacterial activity of N-substituted piperazinyl quinolones 5aÁ
/
l expressed as the MIC
Compound
Ar
X
R
MIC (mg/ml)
E. coli
ATCC8739
K. pneumoniae
ATCC10031
P. aeruginosa
ATCC9027
B. subtilis
PTCC1023
S. aureus
ATCC6538P
S. epidermidis
ATCC12228
5a
5b
5c
1-methyl-5-nitro-2-imida- CH Cpr a
zolyl
2
2
ꢀ
/
64
32
64
ꢀ
/
64
64
64
0.015
0.015
0.03
0.008
0.03
0.008
0.015
0.015
8
1-methyl-5-nitro-2-imida- CH Et
zolyl
ꢀ/
1-methyl-5-nitro-2-imida-
zolyl
N
Et
32
ꢀ/
ꢀ/
0.015
16
5d
5e
5f
2-nitrophenyl
2-nitrophenyl
2-nitrophenyl
3-nitrophenyl
3-nitrophenyl
3-nitrophenyl
4-nitrophenyl
4-nitrophenyl
4-nitrophenyl
CH Cpr 16
16
64
32
64
64
64
32
64
64
64
64
64
64
64
64
32
64
64
16
32
64
32
32
16
CH Et
Et
32
32
ꢀ
/
ꢀ
/
64
32
64
64
64
32
64
64
ꢀ
/
64
8
N
ꢀ
/
5g
5h
5I
5j
CH Cpr 32
ꢀ
/
16
64
64
32
64
64
CH Et
Et
32
32
ꢀ/
ꢀ
/
ꢀ
/
ꢀ/
N
ꢀ/
ꢀ/
CH Cpr 32
ꢀ
/
64
64
64
5k
5l
CH Et
Et
32
64
ꢀ
/
ꢀ
/
ꢀ
/
ꢀ
/
N
ꢀ/
ꢀ/
ꢀ/
ꢀ/
ꢀ/
Ciprofloxacin
Norfloxacin
Enoxacin
0.06
0.06
0.5
0.008
0.5
0.25
0.25
0.13
0.25
0.25
4
4
0.06
0.13
1
0.5
1
0.5
a
Cyclopropyl.

A. Foroumadi et al. / Il Farmaco 58 (2003) 1023Á
/
1028
1027
2.2.12. 1-Ethyl-6-fluoro-7-{4-[5-(4-nitrophenyl)-1,3,4-
thiadiazole-2-yl]-1-piperazinyl}-4-oxo-1,4-dihydro-1,8-
naphthyridine-3-carboxylic acid (5l)
[13]. Reaction of the latter with piperazinyl quinolones
(4aÁc) in DMF afforded compounds 5aÁl (Scheme 1).
The antibacterial activity of 5aÁl was assessed in side-
/
/
/
This compound was prepared as described for 5c in
95% yield, reaction time: 10 h, temperature: 120 8C, m.p.
by-side comparison with ciprofloxacin, norfloxacin and
enoxacin against some Gram-positive and Gram-nega-
tive bacteria using conventional agar dilution procedure,
and the results are summarized in Table 1. The
antibacterial data indicated that the nitroimidazole
derivatives had significant activity against tested
342Á
(CÄ
O) and 1536, 1357/cm (NO2). 1H NMR (DMSO-d6,
500 MHz) d: 9.01 (s, 1H, H2-quinoline), 8.34 (d, 2H,
/
346 8C (dec.) (DMF). IR (KBr) nmax: 1721, 1630
/
phenyl, Jꢀ
Hz), 8.08 (d, 2H, phenyl, Jꢀ
Jꢀ7.1 Hz), 4.08Á4.05 (m, 4H, piperazine), 3.84Á
(m, 4H, piperazine), 1.43 ppm (t, 3H, CH3, Jꢀ
/
8.6 Hz), 8.17 (d, 1H, H5-quinoline, Jꢀ
/
13.3
/8.6 Hz), 4.55 (q, 2H, CH2,
Gram-positive organisms (MICꢀ
/
0.008Á0.03 mg/ml) in
/
/
/
/
3.82
comparison to the reference drugs, but they did not
show good activity against Gram-negative bacteria
(Table 1). In contrast to the good activity of nitroimi-
dazole analogues, all isomeric nitrophenyl derivatives
showed negligible activity against both Gram-positive
and Gram-negative bacteria.
/7.1 Hz).
2.3. Biological assay
The in vitro antibacterial activity of the tested
compounds was investigated in side-by-side comparison
with ciprofloxacin, norfloxacin and enoxacin against
Gram-negative (Escherichia coli, Klebsiella pneumoniae
and Pseudomonas aeruginosa) and Gram-positive (Sta-
phylococcus aureus and Staphylococcus epidermidis and
Bacillus subtilis) bacteria using conventional agar dilu-
tion procedures [12].
The MIC values of tested derivatives indicated that
ciprofloxacin analogue in nitroimidazole series (5a) was
the most active compound against S. aureus and S.
epidermidis (MICꢀ0.008 mg/ml).
/
In addition 5a in comparison to ciprofloxacin was 62
times more potent against S. aureus and 31 times more
potent against S. epidermidis.
In vitro antibacterial evaluation indicated that the
Twofold serial dilutions of the tested compounds and
nitroimidazole derivatives 5aÁc possess similar antibac-
/
reference drugs were prepared in MullerÁHinton agar.
/
terial profiles as compared to their nitrofuran counter-
parts [7].
Drugs (6.4 mg) were dissolved in dimethylsulfoxide
(DMSO, 1 ml) and the solution was diluted with distilled
water (9 ml). Further progressive double dilutions with
melted MullerÁHinton agar were performed to obtain
/
Acknowledgements
the required concentrations of 64, 32, 16, 8, 4, 2, 1, 0.5,
0.25, 0.13, 0.06, 0.03, 0.015, 0.008 and 0.004 mg/ml. Petri
5ꢁ
104 colony forming
/
This research was partially supported by the Research
Council of Medical Sciences University of Kerman,
Iran.
dishes were inoculated with 1Á
/
units and incubated at 37 8C for 18 h. The minimum
inhibitory concentration (MIC) was the lowest concen-
tration of the tested compound and yielded 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 supplemented with DMSO at the same
dilutions as used in the experiments.
References
[1] M.T. Mascellino, S. Farinelli, F. Iegri, E. Iona, C. De Simone,
Antimicrobial activity of fluoroquinolones and other antibiotics
on 1116 clinical gram-positive and gram-negative isolates, Drug.
Exp. Clin. Res. 24 (1998) 139Á
[2] D.C Hooper, Mechanisms of action of antimicrobials: focus on
fluoroquinolones, Clin. Infect. Dis. 32 (2001) S9ÁS15.
/
151.
3. Results and discussion
/
[3] K.C. Fang, Y.L. Chen, J.Y. Sheu, T.C. Wang, C.C. Tzeng,
Synthesis, antibacterial and cytotoxic evaluation of certain 7-
substituted norfloxacin derivatives, J. Med. Chem. 43 (2000)
A
series of N-[5-(1-methyl-5-nitro-2-imidazolyl)-
1,3,4-thiadiazole-2-yl] and N-[5-(nitrophenyl)-1,3,4-
thiadiazole-2-yl] piperazinyl quinolone derivatives (5aÁ
c and 5dÁl) were synthesized according to Scheme 1.
The 2-amino-5-aryl-1,3,4-thiadiazoles (2aÁd) were ob-
3809Á3812.
/
/
[4] C.S. Cooper, M.D. Tufano, P.K. Donner, D.T. Chu, The
synthesis and in vitro antibacterial activity of conformationally
restricted quinolone antibacterial agents, Bioorg. Med. Chem. 4
/
/
tained from 1-methyl-5-nitroimidazolecarboxaldehyde
thiosemicarbazone (1a) by refluxing in aqueous ammo-
nium ferric sulfate solution [13], or by direct cyclization
(1996) 1307Á1315.
[5] D.C. Hooper, J.S. Wolfson, Quinolone Antimicrobial Agents,
second ed., American Society for Microbiology, Washington, DC,
/
1993, pp. 3Á15.
/
of an arylcarboxylic acid (1bÁd) and thiosemicarbazide
/
[6] L.L. Shen, L.A. Mitscher, P.N. Sharma, T.J. O’ Donell, D.W.T.
Chu, C.S. Cooper, T. Rosen, A.G. Pernet, Mechanism of
inhibition of DNA gyrase by quinolone antibacterials, Biochem-
in phosphorous oxychloride [14]. Diazothiazation of
amines 2 in hydrochloric acid in the presence of copper
powder gave 2-chloro-5-aryl-1,3,4-thiadiazoles 3aÁ
/
d
istry 28 (1989) 3886Á3894.
/

1028
A. Foroumadi et al. / Il Farmaco 58 (2003) 1023Á1028
/
[7] A. Foroumadi, R. Ashraf-Askari, M.H. Moshafi, S. Emami, A.
Zeynali, Synthesis and in vitro antibacterial activity of N-[5-(5-
nitro-2-furyl)-1,3,4-thiadiazole-2-yl]piperazinyl quinolone deriva-
[11] A.H. Lau, N.P. Lam, S.C. Piscitelli, L. Wilkes, L.H. Danziger,
Clinical pharmacokinetics of metronidazole and other nitro-
imidazole anti-infectives, Clin. Pharmacokinet. 23 (1992) 328Á
/
tives, Pharmazie 58 (2003) 432Á
/
433.
364.
[12] E.J. Baron, S.M. Finegold, Bailey & Scott’s Diagnostic Micro-
[8] F.A. Ashour, N.S. Habib, M. Taibbi, S. Dine, A. Dine, Synthesis
of 1,3,4-thiadiazoles,imidazo[2,1-b]1,3,4-thiadiazoles and thiadia-
zolo[3,2-a]pyrimidines derived from benzimidazole as potential
biology, eighth ed., The C.V. Mosby Company, 1990, pp. 171Á
/
194.
antimicrobial agents, Farmaco 45 (1990) 134Á
/
139.
[13] A. Foroumadi, M. Daneshtalab, A. Shafiee, Synthesis and in vitro
antifungal activity of 2-aryl-5-phenylsulfonyl-1,3,4-thiadiazole
[9] S. Rollas, S. Karakus, B.B. Durgun, M. Kiraz, H. Erdeniz,
Synthesis and antimicrobial activity of some 1,4-disubstituted
thiosemicarbazide and 2,5-disubstituted 1,3,4-thiadiazole deriva-
derivatives, Arzneim. Forsch. Drug Res. 49 (1999) 1035Á
[14] I. Lalezari, A. Shafiee, Selenium heterocycles. IV. Synthesis of
2-amino-1,3,4-selenadiazole and 2-substituted-6-phenylimi-
dazo[2,1-b]-1,3,4-selenadiazoles, J. Heterocyclic Chem. 8 (1971)
835Á837.
/1038.
tives, Farmaco 51 (1996) 811Á
[10] C.D. Freeman, N.E. Klutman, K.C. Lamp, Metronidazole a
therapeutic review and update, Drugs 54 (1997) 679Á708.
/814.
/
/