Synthesis, characterization and biological evaluation of some novel fluoroquinolones

Article abstract of DOI:10.1007/s00044-016-1526-x

Different derivatives of fluoroquinolones were synthesized by combining it with different thiadiazoles. The synthesized compounds were characterized by infrared spectroscopy, proton nuclear magnetic resonance and mass spectral data. The compounds were screened for their antibacterial and antifungal activity. Ciprofloxacin derivatives with thiadiazoles 7c showed good antibacterial as well as antifungal activities, whereas 13c and 13e showed antibacterial and antifungal activity respectively. Sparfloxacin derivative 8c showed both antibacterial and antifungal activity. Sparfloxacin derivatives 14b and 14e showed antibacterial and antifungal activity respectively.

Full text of DOI:10.1007/s00044-016-1526-x

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-016-1526-x
ORIGINAL RESEARCH
Synthesis, characterization and biological evaluation of some
novel fluoroquinolones
1
1
1
2
3
•
Neelanjana Pandit
1
Pradeep Mishra
•
Kamal Shah
•
Neetu Agrawal
•
Neeraj Upmanyu
•
Sushant K. Shrivastava
Received: 14 July 2015 / Accepted: 4 February 2016
Ó Springer Science+Business Media New York 2016
Abstract Different derivatives of fluoroquinolones
were synthesized by combining it with different thiadi-
azoles. The synthesized compounds were characterized
by infrared spectroscopy, proton nuclear magnetic reso-
nance and mass spectral data. The compounds were
screened for their antibacterial and antifungal activity.
Ciprofloxacin derivatives with thiadiazoles 7c showed
good antibacterial as well as antifungal activities,
whereas 13c and 13e showed antibacterial and antifungal
activity respectively. Sparfloxacin derivative 8c showed
both antibacterial and antifungal activity. Sparfloxacin
derivatives 14b and 14e showed antibacterial and anti-
fungal activity respectively.
Staphylococcus epidermis. Furthermore, most of them are
active against Hemophilus influenza, Providencia rettgeri,
Pseudomonas aeruginosa, Serratia marcescens, Staphylo-
coccus aureus, Enterococcus fecalis, Mycoplasma pneu-
moniae, Chlamydia pneumoniae and Neisseria gonorrheae.
Thiadiazole is a five-membered heterocyclic compound
which acts as ‘‘hydrogen-binding domain’’ and ‘‘two-
electron donor system’’(Kempegowda et al., 2011). 1,3,4-
Thiadiazole derivatives possess interesting biological
activity probably conferred to them due to strong aro-
maticity of the ring system which leads to great in vivo
stability and, generally, a lack of toxicity for higher
vertebrates, including humans, when diverse functional
groups that interact with biological receptor are
attached to thiadiazole ring. The reported studies
showed broad-spectrum antimicrobial (Marquez et al.,
Keywords Floroquinolones Á Antimicrobial Á
Ciprofloxacin Á Sparfloxacin Á Antifungal
2
014; Al-Zoubi et al., 2014; Chen et al., 2007; Swamy
et al., 2006; Qandil et al., 2006), antihypertensive
(Samel and Pai, 2010), anticonvulsant (Sharma et al.,
Introduction
2
013), hypoglycemic (Datar and Deokule, 2014),
Fluoroquinolones are important broad-spectrum antibacte-
rial agents. They are active against species such as Enter-
obacter, Proteus mirabilis, Morganella morganii and
anthelmentic (Sukla et al., 1983), anticancer (Noolvi
et al., 2011), antiulcerogenic (Tweit, 1973) activities of
thiadiazole.
As triazoles (Huang et al., 2010), oxadiazoles
(Kumar et al., 2011), piperidines (Yunchai et al., 2010),
nitro aryl thiadiazoles (Senthilkumar et al., 2009) coupled
with fluoroquinolones showed good antimicrobial activity.
So, it was thought worthwhile to synthesize some newer
derivatives of thiadiazole, coupled them with fluoro-
quinolones and evaluate them for their antimicrobial
activity. Here known compound ciprofloxacin and
sparfloxacin were coupled with different derivatives of
thiadiazoles with keeping aim to show promising antimi-
crobial activity and least toxicity (Figs. 1, 2).
&
Kamal Shah
kamal0603@gmail.com
1
Institute of Pharmaceutical Research, GLA University,
NH # 2, Delhi-Mathura Road, Post: Chaumuhan, Mathura,
U.P. 281406, India
2
3
School of Pharmacy and Research, Peoples University,
Bhopal, M.P. 462037, India
Department of Pharmaceutics, Institute of Technology,
Banaras Hindu University, Varanasi, U.P. 221005, India
123

Med Chem Res
O
N
dioxane with reflux condenser, and dropping funnel contained
chloro acetyl chloride (0.05 mol, 5.64 mL) in 10 mL of
dioxane. The round-bottom flask was heated with the help of
heating mantel. The whole assembly was housed in fume
cupboard, and while refluxing the contents of flask, the chloro
acetyl chloride solution was slowly added to it. The refluxing
was continued for half an hour, after the complete addition of
chloroacetyl chloride. The content was cooled and poured on
crushed ice. The crude product thus precipitated was filtered,
washed with ice-cold water and recrystallized from ethanol
F
COOH
N
N
N
R
S
NHCOCH
2
N
Fig. 1 Ciprofloxacin derivatives
(
95 %v/v) to give the compounds 6a–d.
The compounds 6a–d (0.012 mol) and sodium bicar-
NH2
O
F
COOH
bonate (0.012 mol, 1.00 g) in dimethylformamide (30 mL)
were heated under reflux at 90 °C for 6 h with cipro-
floxacin (0.012 mol, 3.96 g) and sparfloxacin (0.012 mol,
H C
3
N
N
N
N
4
.68 g) to give 7a–d and 8a–d (Scheme 1), respectively.
N
F
R
NHCOCH2
The solvent was removed under reduced pressure. Water
was added to the residue; solid was filtered, washed with
water and recrystallized with DMF–water.
S
CH3
Fig. 2 Sparfloxacin derivatives
2
1
-[Amino acetyl 1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-
-yl-quinoline-3-carboxylic acid]-5-methyl thiadiazole
Materials and methods
Chemistry
(7a) White crystals; yield: 54.5 %; m.p.: 308°–313°; IR
-1
(
KBr, cm ): 3111.18 (N–H str), 3062.96 (Ar C–H str),
2234.38 (C–S str), 1796.38 (C=O str), 1635.64 for C=O,
456.26 for ring (Ar–C=O str), 1456.20 (–CH2 bend),
1
Melting points of the newly synthesized compounds were
determined by open capillary method and were uncor-
1336.37 (C–F str), 1275.25 (Aliph C–N str), 927.56 (N–N
1
str); H NMR (CDCl , d, ppm): d = 7.981 (s, 1H; Ar–H),
3
rected. IR spectra were recorded on Shimadzu IR Affinity-
1
FTIR spectrophotometer. H NMR spectra were recorded
10.927 (s, 1H; –COOH), 7.094 (s, 1H; Ar–H), 3.369–3.450
1
(t, 4H; 2-CH ), 2.496–2.592 (t, 4H; 2CH ), 3.245 (s, 2H;
2
2
on Bruker DPX-300 MHz NMR spectrophotometer with
–CH ), 7.993 (s, 1H; –NH), 2.359 (s, 3H; –CH ), 5.921 (s,
2 3
CDCl as solvent. Chemical shifts (d) were reported in
1H; Ar–H), 1.294–1.356 (t, 2H; –CH ), 0.491–0.529 (m,
2
3
parts per million (ppm) relative to internal TMS. Splitting
2H; [–CH] ), 0.263–0.279 (m, 2H; [–CH] ); Mass (ESI, m/
2
2
?
z): M = 486.527.
patterns were designated as singlet (s), doublet (d), triplet
(
t), quartet (q) and multiplet (m). The mass spectra were
recorded on a Bruker Daltonics micro TOF-Q II by using
ESI) method. Reagents and solvents were purchased from
2
1
-[Amino acetyl 1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-
-yl-quinoline-3-carboxylic acid]-5-propyl thiadiazole
(
(
7b) Light yellow crystals; yield: 63.9 %; mp.: 320°–
23°; IR (KBr, cm ): 3111.18 (N–H str), 3062.96 (Ar
common commercial suppliers and were used without
further purification unless stated otherwise.
-
1
3
C–H str), 2234.38 (C–S str), 1796.38 (C=O str), 1635.64
for C=O, 1456.26 for ring (Ar–C=O str), 1456.20 (–CH2
General procedure for the synthesis of 7a–d and
a–d
bend), 1336.37 (C–F str), 1275.25 (Aliph C–N str), 927.56
1
8
(
N–N str); H NMR (CDCl , d, ppm): d = 7.962 (s, 1H;
3
Ar–H), 11.013 (s, 1H; –COOH), 7.125 (s, 1H; Ar–H),
A well-stirred mixture of fatty acids 4a–d (0.1 mol), con-
centrated sulfuric acid (25 mL) and thiosemicarbazide
3.224–3.420 (t, 4H; 2-CH ), 2.540–2.597 (t, 4H; 2-CH ),
2 2
3.356 (s, 2H; –CH ), 8.470 (s, 2H; –NH), 2.464–2.492
2
(
3)(0.1 mol, 9.1 g) was slowly heated to 80–90 °C and
(t, 2H; –CH ), 1.591–1.620 (t, 3H; –CH ), 1.311–1.337 (t, 2H;
2 3
maintained at that temperature for 7 h. After cooling, it was
poured on crushed ice with constant stirring and then made
alkaline with ammonia. The crude product thus precipitated
was filtered, washed with ice-cold water and recrystallised
from aqueous ethanol (70 %v/v) to give compounds 5a–d.
The compounds 5a–d (0.05 mol) were taken in a two-
necked round-bottomed flask fitted containing 100 mL of
–
1
0
CH ), 0.939–0.957 (t, 3H; –CH ), 5.931 (s, -1H; Ar–H),
2 3
.359 (t, 2H; –CH ), 0.491–0.529 (m, 2H; [–CH] ),
2
2
?
.263–0.279 (m, 2H; [CH] ); Mass (ESI, m/z): M = 514.185.
2
2-[Amino acetyl 1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-
1-yl-quinoline-3-carboxylic acid]-5-hexyl thiadiazole
(7c) Brown needle-shaped crystals; yield: 77.4 %, m.p.:
1
23

Med Chem Res
Scheme 1 Synthesis of
compounds 7a–d and 8a–d
S
N
N
H SO
2 4
RCOOH
(4a-d)
H N
2
N
H
NH2
R
NH2
S
(
3)
(5a-d)
ClCH COCl
2
N
N
R
NHCOCH Cl
S
2
(
6a-d)
n
i
c
a
x
o
l
f
S
p
a
o
r
p
i
r
C
f
l
o
x
a
c
i
NH2
O
N
n
F
COOH
N
N
N
NH2
O
N
F
COOH
R
S
NHCOCH2
N
(7a-d)
N
N
CH3
N
F
(8a-d)
R
NHCOCH2
N
a, R= CH3-
b, R= CH CH
c, R= CH CH CH CH CH CH -
S
3
2 2
CH -
3
2
2
2
2
2
d, R= CH CH CH CH -
CH3
3
2
2
2
-
1
2
89°–292°; IR (KBr, cm ): 3111.18 (N–H str), 3062.96 (Ar
C–H str), 2234.38 (C–S str), 1796.38 (C=O str), 1635.64 for
7.120 (s, 1H; Ar–H), 3.413–3.457 (t, 2H; –CH2),
2.561–2.595 (t, 2H; –CH ), 3.256 (s, 2H; –CH ), 7.982 (s,
2
2
C=O, 1456.26 for ring (Ar C=O str), 1456.20 (–CH bend),
2
1H; –NH), 2.517–2.551 (t, 2H; –CH ), 1.596–1.628 (t, 2H;
2
1
336.37 (C–F str), 1275.25 (Aliph C–N str), 927.56 (N–N
1
–CH ), 1.230–1.291 (t, 2H; –CH ), 1.304–1.332 (t, 2H;
2
2
str), 745.56 ([–CH ] ); H NMR (CDCl , d, ppm): d = 7.96
–CH ), 0.947–0.968 (t, 3H; –CH ), 5.931 (s, 1H; Ar–H),
2 3
2
6
3
?
(
s, 1H; Ar–H), 11.013 (s, 1H; –COOH), 7.127 (s, 1H;
1.344–1.351 (t, 1H; –CH); Mass (ESI, m/z): M = 528.634.
5-amino-1-cyclopropyl-7-[(3R,5S)3,5-dimethylpiperazin-
-yl]-6,8-difluoro-4-oxo-quinoline-3-carboxylicacid]-5-
Ar–H), 3.374–3.458 (t, 4H; 2-CH ), 2.571–2.596 (t, 4H;
2
[
2
2
1
0
-CH ), 3.252 (s, 2H; –CH ), 8.012 (s, 1H; –NH),
2 2
1
.490–2.569 (t, 2H;–CH ), 1.598–1.624 (t, 2H; –CH ),
2
2
methyl thiadiazole (8a) Yellow needle-shaped crystals;
-1
.216–1.291 (t, 6H; 3-CH ), 1.318–1.336 (t, 2H; –CH ),
2
2
yield: 62.4 %; m.p.: 256°–259°; IR (KBr, cm ): 3412 &
.939–0.957 (t, 3H; –CH ), 5.931 (s, 1H; –CH), 1.349–1.359
3
3
189 (–NH bend), 3111.18 (N–H str), 3062.96 (Ar C–H
2
(
t, 1H; CH), 0.491–0.529 (m, 2H; [–CH] ), 0.263–0.279 (m,
2
str), 2234.38 (C–S str), 1796.38 (C=O str), 1635.64 for
C=O, 1456.26 for ring (Ar–C=O str), 1456.20 (–CH2
?
H; [–CH] ); Mass (ESI, m/z): M = 556.605.
2
2
2
1
-[Amino acetyl 1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-
-yl-quinoline-3-carboxylic acid]-5-butyl thiadiazole (7d)
bend), 1389.53 (–CH bend), 1336.37 (C–F str), 1275.25
3
1
(Aliph C–N str), 927.56 (N–N str); H NMR (CDCl , d,
3
Pale-yellow needle-shaped crystals; yield: 81.0 %; m.p.:
ppm): d = 7.967 (s, 1H; Ar–H), 11.015 (s, 1H; –COOH),
3.992 (s, 2H; –NH ), 3.530–3.546 (d, 2H; [–CH] ),
-
1
2
68°–271°; IR (KBr, cm ): 3111.18 (N–H str), 3062.96
Ar C–H str), 2234.38 (C–S str), 1796.38 (C=O str),
635.64 for C=O, 1456.26 for ring (Ar–C=O str), 1456.20
–CH bend), 1336.37 (C–F str), 1275.25 (Aliph C–N str),
2
2
(
3.273–3.298 (d, 2H; [CH] ), 2.983–3.039 (m, H; –CH),
2
1
1.086–1.103 (d, 6H; [–CH ] ), 3.255 (s, 2H; –CH ), 8.012
3
2
2
(
(s, 1H; –NH), 2.358 (s, 3H; –CH ), 1.347–1.352 (t, 1H;
3
2
1
9
27.56 (N–N str), 745.56 ([–CH ] ); H NMR (CDCl , d,
–CH), 0.263–0.279 (m, 2H; [–CH] ), 0.491–0.529 (m, 2H;
2
2
4
3
?
[–CH] ); Mass (ESI, m/z): M = 547.062.
ppm): d = 7.964 (s, 1H; Ar–H), 10.927 (s, 1H; –COOH),
2
123

Med Chem Res
[
5-amino-1-cyclopropyl-7-[(3R,5S)3,5-dimethylpiperazin-
-yl]-6,8-difluoro-4-oxo-quinoline-3-carboxylicacid]-5-
propyl thiadiazole (8b) Yellow needle-shaped crystals;
1.356–1.343 (t, H; –CH), 0.263–0.279 (m, 2H; [–CH]2),
1
0.491–0.529 (m, 2H; [–CH]2); Mass (ESI, m/z):
?
M = 589.663.
-
1
yield: 62.4 %; m.p.: 279°–283°; IR (KBr, cm ): 3412 &
189 (–NH bend), 3111.18 (N–H str), 3062.96 (Ar C–H
3
2
General procedure for the synthesis of 7a–d and
8a–d
str), 2234.38 (C–S str), 1796.38 (C=O str), 1635.64 for
C=O, 1456.26 for ring (Ar–C=O str), 1456.20 (–CH2
bend), 1389.53 (–CH bend), 1336.37 (C–F str), 1275.25
3
Aromatic aldehyde (0.1 mol) (9a–e) in warm alcohol
300 mL) and a solution of thiosemicarbazide (0.1 mol) in
00 mL of hot water were mixed slowly with continuous
1
(
Aliph C–N str), 927.56 (N–N str); H NMR (CDCl , d,
3
(
ppm): d = 7.967 (s, 1H; Ar–H), 11.015 (s, 1H; –COOH),
3
4
3
1
.097 (s, 2H; –NH ), 3.521–3.542 (d, 1H; –CH),
2
stirring. The product which separated after cooling was
filtered off and recrystallized from appropriate solvents to
give 10a–e.
.268–3.291 (d, 1H; –CH), 2.957–3.035 (m, 1H; –CH),
.063–1.108 (d, 6H; [–CH ] ), 3.252 (s, 2H; –CH ), 8.012
3
2
2
(
s, 1H; –NH), 2.497–2.556 (t, 2H; –CH ), 1.607–1.624 (t,
2
10a–e (0.05 mol, g) was suspended in 300 mL distilled
2
H; –CH ), 1.311–1.330 (t, 2H; –CH ), 0.917–0.968 (t 3H;
2 2 ,
water, and a solution of ferric chloride (0.15 mol, 24.33 g)
in 300 mL of distilled water was added to it. This was
heated to 80–90 °C and maintained for 3 h. Then, solution
was filtered and cooled. A mixture of citric acid (0.11 mol,
21.1 g) and sodium citrate (0.05 mol, 12.9 g) was dis-
solved in minimum amount of distilled water and added to
filtered mixture and stirred. After cooling, the whole
solution was divided into four parts, and then, neutraliza-
tion was affected by 10 % ammonia. The precipitate so
obtained was filtered and washed with distilled water and
allowed to dry to give 11a–e. Crystallization was done
using appropriate solvent.
–
CH ), 1.343–1.356 (t, 1H; –CH), 0.263–0.279 (m, 2H;
3
[
–CH] ), 0.491–0.529 (m, 2H; [–CH] ); Mass (ESI, m/z):
2 2
?
M = 575.208.
5-amino-1-cyclopropyl-7-[(3R,5S)3,5-dimethylpiperazin-
-yl]-6,8-difluoro-4-oxo-quinoline-3-carboxylicacid]-5-
hexylthiadiazole (8c) Yellow needle-shaped crystals;
[
1
-
1
yield: 82.6 %; m.p.: 346°–348°; IR (KBr, cm ): 3412
3189 (–NH bend), 3111.18 (N–H str), 3062.96 (Ar C–H
&
2
str), 2234.38 (C–S str), 1796.38 (C=O str), 1635.64 for
C=O, 1456.26 for ring (Ar–C=O str), 1456.20 (–CH2
bend), 1389.53 (–CH bend), 1336.37 (C–F str), 1275.25
3
(
Aliph C–N str), 927.56 (N–N str), 745.56 ([–CH ] ); NMR
6
11a–e (0.025 mol, g) was taken in a two-necked round-
bottom flask containing 100 mL dry benzene, fitted with
reflux condenser and a dropping funnel containing chlor-
oacetyl chloride (0.025 mol, 2.82 mL). Chloroacetyl
chloride was added dropwise with stirring. After the total
addition, contents were refluxed for 3 h. The solvent was
distilled off, and the product so obtained was taken out of
the round-bottom flask with aid of appropriate solvent and
poured on crushed ice. The product was filtered off and
washed several times with cold distilled water to free it
from chloride to give 12a–e. Crystallization was done
using appropriate solvent.
2
(
CDCl , d, ppm): d = 7.967 (s, 1H; Ar–H), 11.467 (s, 1H;
3
–
3
1
COOH), 4.097 (s, 1H; –NH ), 3.521–3.542 (d, 1H; –CH),
2
.268–3.291 (d, 1H; –CH), 2.957–3.035 (m, 1H; –CH),
.062–1.108 (d, 6H; [–CH ] ), 3.252 (s, 2H; –CH ), 8.012
3
2
2
(
s, 1H; –NH), 2.497–2.556 (t, 2H; –CH ), 1.578–1.624 (t,
2
2
2
–
H; –CH ), 1.263–1.290 (t, 6H; [–CH ] ), 1.309–1.330 (t,
2 2 3
H; –CH ), 0.917–0.968 (t, 3H; –CH ), 1.343–1.356 (t, 1H;
2
3
CH), 0.264–0.279 (m, 2H; [–CH] ), 0.491–0.529 (m, 2H;
2
?
[
–CH] ); Mass (ESI, m/z): M = 617.707.
2
[
5-amino-1-cyclopropyl-7-[(3R,5S)3,5-dimethylpiperazin-
-yl]-6,8-difluoro-4-oxo-quinoline-3-carboxylicacid]-5-
butyl thiadiazole (8d) Yellow needle-shaped crystals;
1
12a–e (0.025 mol) and ciprofloxacin (0.03 mol, 9.94 g) or
sparfloxacin (0.015 mol, 5.85 g) were taken in round-bottom
flask containing dry benzene 100 mL and dry pyridine
-
1
yield: 74.6 %; m.p.: 309°–312°; IR (KBr, cm ): 3412 &
189 (–NH bend), 3111.18 (N–H str), 3062.96 (Ar C–H
3
2
(0.025 mol, 0.94 mL) to give 13a–e or 14a–e (Scheme 2),
str), 2234.38 (C–S str), 1796.38 (C=O str), 1635.64 for
respectively. The content was refluxed for 48 h on an elec-
trically heated water bath. The solvent was distilled off and
product dried under reduced pressure in a rotary vacuum
evaporator. The dried product so obtained was taken out of
flask with the aid of appropriate solvent and poured on cru-
shed ice. The product was filtered off and washed several
times with cold distilled water to free it from chloride. The
crystallization was done using appropriate solvent.
C=O, 1389.53 (–CH bend), 1456.26 for ring (Ar–C=O
3
str), 1456.20 (–CH bend), 1336.37 (C–F str), 1275.25
2
(
Aliph C–N str), 927.56 (N–N str), 745.56 ([–CH ] ); NMR
2 4
(
CDCl , d, ppm): d = 7.967 (s, 1H; Ar–H), 11.467 (s,
3
1
–
–
8
1
1
H;COOH), 4.097 (s, 2H; NH ), 3.521–3.542 (d, 1H;
2
CH), 3.268–3.291 (d, 1H; –CH), 2.961–3.035 (m, 1H;
CH), 1.062–1.108 (d, 6H; [–CH ] ), 3.252 (s, 2H; –CH ),
3
2
2
.012 (s, 1H; –NH), 2.497–3.556 (t, 2H; –CH2),
.578–1.624 (t, 2H; –CH ), 1.263–1.290 (t, 2H; –CH ),
2-[Amino acetyl 1-cyclopropyl-6-fluoro-4-oxo- 7-piper-
azin-1-yl-quinoline-3-carboxylic acid]-(5-phenyl)-1,3,4-
2
2
.309 = 1.330 (t, 2H; –CH ), 0.917–0.968 (t, 3H; –CH ),
2
3
1
23

Med Chem Res
Scheme 2 Synthesis of
compounds 13a–e and 14a–e
R2
R
2
2
H NNHCSNH2
R1
CH=NNHCSNH2
R1
CHO
(10a-e)
(9a-e)
Ferric Chloride
R
2
N
N
R
2
N
N
lo
ClCOCH Cl
2
R1
S
NH2
R1
S
NHCOCH Cl
2
(
11a-e)
(12a-e)
S
p
ar
NH2
O
f
x
a
c
in
F
COOH
N
N
H
3
C
N
N
R2
R1
F
NHCOCH2
N
S
(
14a-e)
CH3
O
F
COOH
N
N
N
N
R
2
NHCOCH
2
N
S
a, R = H, R = H
(13a-e)
1
2
R
1
1 2
b, R = H, R = Cl
c, R = Cl, R = H
1
2
d, R = H, R = NO
1
2
2
e, R = OCH , R = OCH
1
3
2
3
thiadiazole (13a) Light-green crystals; yield: 62.1 %;
(Ar C–H str), 3056.82 (=C–H stre), 2234.38 (C–S str),
1796.38 (C=O str), 1635.64 for C=O, 1456.26 for ring
(Ar–C=O str), 1456.20 (–CH2 bend), 1498 (C=C str),
1336.37 (C–F str), 1275.25 (Aliph C–N str), 927.56 (N–N
str), 864.79 (ortho-substitution), 510.84 (C–Cl); NMR
-
1
m.p.: 326°–329°; IR (KBr, cm ): 3111.18 (N–H str),
062.96 (Ar C–H str), 3056.82 (=C–H str), 2234.38 (C–S
str), 1796.38 (C=O str), 1635.64 for C=O, 1456.26 for ring
Ar–C=O str), 1489.20 (–CH2 bend), 1498 (C=C str),
336.37 (C–F str), 1275.25 (Aliph C–N str), 927.56 (N–N
str); NMR (CDCl , d, ppm): d = 7.967 (S, 1H; Ar–H),
3
(
1
(CDCl , d, ppm): d = 7.967 (S, 1H; Ar–H), 10.980 (s, 1H;
3
–COOH), 7.126 (s, 2H; –NH ), 3.402–3.489 (t, 2H; –CH ),
2
3
2
1
0.980 (s, 1H; –COOH), 7.126 (s, 2H; –NH ), 3.402–3.489
2
2.562–2.681 (t, 2H; –CH ), 3.252 (s, 2H; CH ), 8.102
2 2
(
t, 2H; –CH ), 2.562–2.681 (t, 2H; –CH ), 3.252 (s, 2H;
2
(s, 1H; –NH), 7.485 (s, 1H; CH), 7.228–7.237 (d, H; –CH),
7.237–7.263 (t, H; –CH), 7.351–7.366 (d, H; CH), 5.930
(s, 1H; Ar–H), 1.318–1.357 (t, 1H; Ar–H), 0.263–0.279
(q, 2H; [CH ]), 0.491–0.529 (q, 2H; [CH] ); Mass (ESI,
2
CH ), 8.102 (s, 1H; –NH), 7.401–7.485 (d, 2H; [Ar–H] ),
2
2
7
5
0
.313–7.329 (d, 2H; [Ar–H] ), 7.214–7.228 (d, 1H; Ar–H),
2
.930 (s, 1H; Ar–H), 1.318–1.357 (t, 1H; Ar–H),
.263–0.279 (q, 2H; [CH ]), 0.491–0.529 (q, 2H; [CH] );
2
2
?
m/z): M = 582.135.
2
2
?
Mass (ESI, m/z): M = 548.632.
2
-[Amino acetyl 1-cyclopropyl-6-fluoro-4-oxo- 7-piper-
2
-[Amino acetyl 1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-
-yl-quinoline-3-carboxylic acid]-5-(3-chlorophenyl)-1,3,4-
azin-1-yl-quinoline-3-carboxylic acid]-5-(4-chloropheny)l-
1,3,4-thiadiazole (13c) White crystals; yield: 64.6 %;
1
-
1
thiadiazole (13b) White crystals; yield: 69.3 %; m.p.:
-
3
m.p.: 330°–333°; IR (KBr, cm ): 3111.18 (N–H str),
3062.96 (Ar C–H str), 3056.82 (=C–H str), 2234.38 (C–S
1
08°–309°; IR (KBr, cm ): 3111.18 (N–H str), 3062.96
123

Med Chem Res
str), 1796.38 (C=O str), 1635.64 for C=O, 1456.26 for ring
Ar–C=O str), 1412.20 (–CH2 bend), 1498 (C=C str),
336.37 (C–F str), 1275.25 (Aliph C–N str), 927.56 (N–N
str), 746.79 (meta-substitution), 510.84 (C–Cl); NMR
CDCl , d, ppm): d = 7.967 (S, 1H; Ar–H), 10.980 (s, 1H;
str), 1796.38 (C=O str), 1635.64 for C=O, 1389.53 (–CH3
bend), 1456.26 for ring (Ar–C=O str), 1456.20 (–CH2
bend), 1498 (C=C str), 1336.37 (C–F str), 1275.25 (Aliph
(
1
C–N str), 927.56 (N–N str); NMR (CDCl , d, ppm):
3
(
d = 7.96 (s, 1H; Ar–H), 10.980 (s, 1H; COOH), 3.992 (s,
2H; NH ), 3.530–3.546 (d, 1H; –CH), 3.273–3.298 (d, 1H;
3
–
2
1
5
0
COOH), 7.126 (s, 1H; Ar–H), 3.402–3.489 (t, 2H; –CH2),
2
.562–2.681 (t, 2H; –CH ), 3.252 (s, 2H; –CH ), 8.102 (s,
2
–CH), 2.911–3.039 (m, 1H; –CH), 1.086–1.103 (d, 6H;
[–CH ] ), 3.255 (s, 2H; CH ), 8.612 (s, 1H; –NH),
2
H; –NH), 7.329 (s, H; CH), 7.413–7.420 (s, 4H; 2-CH2),
.930 (s, 1H; Ar–H), 1.318–1.357 (s, 1H. –CH),
.263–0.279 (q, 2H; [CH ]), 0.491–0.529 (q, 2H; [CH] );
3 2
2
7.485–7.489 (d, 2H; [–CH] ), 7.313–7.330 (d, 2H; [–CH] ),
2
2
7.202–7.228 (t, 1H; –CH), 1.318–1.357 (t, 1H; –CH),
0.263–0.279 (q, 2H; [CH ]), 0.491–0.529 (q, 2H; [CH] );
2
2
?
Mass (ESI, m/z): M = 582.133.
-[Amino acetyl 1-cyclopropyl-6-fluoro-4-oxo- 7-piper-
azin-1-yl-quinoline-3-carboxylic acid]-5-(3-nitrophenyl)-
,3,4-thiadiazole (13d) Pale-yellow needle-shaped crys-
2
2
?
Mass (ESI, m/z): M = 609.621.
2
[5-amino-1-cyclopropyl-7-[(3R,5S)3,5-dimethylpiperazin-
1-yl]-6,8-difluoro-4-oxo-quinoline-3-carboxylic acid]-5-
(3-chlorophenyl)-1,3,4 thiadiazole (14b) Pale-yellow
needle-shaped crystals; yield: 60.9 %; m.p.: 289°–293°; IR
1
-
1
tals; yield: 69.8 %; m.p.: 289°–292°; IR (KBr, cm ):
111.18 (N–H str), 3062.96 (Ar C–H str), 3056.82 (=C–H
3
-
1
stre), 2234.38 (C–S str), 1796.38 (C=O str), 1635.64 for
(KBr, cm ): 3412 & 3189 (–NH bend), 3111.18 (N–H
2
C=O, 1522.61 and 1385.17 (–NO )1456.26 for ring
2
str), 3062.96 (Ar C–H str), 3056.82 (=C–H str), 2234.38
(C–S str), 1796.38 (C=O str), 1635.64 for C=O, 1389.53
(–CH3 bend), 1456.26 for ring (Ar–C=O str), 1456.20
(
Ar–C=O str), 1456.20 (–CH2 bend), 1498 (C=C str),
336.37 (C–F str), 1275.25 (Aliph C–N str), 927.56 (N–N
1
str), 864.7 9 (ortho-substitution); NMR (CDCl , d, ppm):
(–CH bend), 1498 (C=C str), 1336.37 (C–F str), 1275.25
2
3
d = 7.967 (S, 1H; Ar–H), 10.980 (s, 1H; –COOH), 7.126
(Aliph C–N str), 927.56 (N–N str), 864.79 (ortho-substi-
(
s, 1H, Ar–H), 3.402–3.489 (t, 2H; –CH ), 2.562–2.681 (t,
2
tution), 510.84 (C–Cl); NMR (CDCl , d, ppm): d = 7.96
3
2
H; –CH ), 3.252 (s, 2H; –CH ), 8.410 (s, 1H; –NH), 8.152
2
(s, 1H; Ar–H), 10.980 (s, 1H; COOH), 3.992 (s, 2H; NH2),
3.530–3.546 (d, 1H; –CH), 3.273–3.298 (d, 1H; –CH),
2.911–3.039 (m, 1H; –CH), 1.086–1.103 (d, 6H; [–CH3]2),
2
(
s, 2H; –CH ), 8.124–8.152 (d, 2H; –CH ), 7.557–7.589 (t,
2 2
2
1
0
H; CH ), 7.843–7.876 (d, 2H; –CH ), 5.907 (s, 1H; Ar–H),
2 2
.318–1.357 (s, 1H. –CH), 0.263–0.279 (q, 2H; [CH ]),
2
3.255 (s, 2H; CH ), 8.005 (s, 1H; –NH), 7.492 (s, 1H;
2
?
.491–0.529(q, 2H; [CH] );Mass(ESI, m/z):M = 593.153.
–CH), 7.235–7.239 (d, 1H; –CH), 7.261–7.263 (t, 1H;
2
–
–
CH), 7.362–7.369 (d, 1H; –CH), 1.318–1.357 (t, 1H;
2
-[Amino acetyl 1-cyclopropyl-6-fluoro-4-oxo- 7-piper-
CH), 0.263–0.279 (q, 2H; [CH ]), 0.491–0.529 (q, 2H;
2
azin-1-yl-quinoline-3-carboxylic acid]-5-(3,4-dimethox-
y)phenyl-1,3,4-thiadiazole (13e) Light-green crystals;
?
CH] ); Mass (ESI, m/z): M = 643.903.
[
2
-
1
yield: 72.5 %; m.p.: 296°–298°; IR (KBr, cm ): 3111.18
N–H str), 3062.96 (Ar C–H str), 3056.82 (=C–H str),
[5-amino-1-cyclopropyl-7-[(3R,5S)3,5-dimethylpiperazin-
1-yl]-6,8-difluoro-4-oxo-quinoline-3-carboxylic acid]-5-
(4-chlorophenyl)-1,3,4 thiadiazole (14c) Pale-yellow
needle-shaped crystals; yield: 49.3 %; m.p.: 292°–295°; IR
(
2
1
234.38 (C–S str), 1796.38 (C=O str), 1635.64 for C=O,
456.26 for ring (Ar–C=O str), 1456.20 (–CH bend), 1498
2
-
1
(
(
C=C str), 1336.37 (C–F str), 1230.74 and 1067.93
(KBr, cm ): 3412 & 3189 (–NH bend), 3111.18 (N–H
2
Ar–OCH ) 1275.25 (Aliph C–N str), 927.56 (N–N str);
3
str), 3062.96 (Ar C–H str), 3056.82 (=C–H str), 2234.38
(C–S str), 1796.38 (C=O str), 1635.64 for C=O, 1389.53
(–CH3 bend), 1456.26 for ring (Ar–C=O str), 1456.20
NMR (CDCl , d, ppm): d = 7.967 (S, 1H; Ar–H), 10.980
3
(
s, 1H; –COOH), 7.126 (s, 2H; –NH ), 3.402–3.489 (t, 2H;
2
–
8
2
5
0
CH ), 2.562–2.681 (t, 2H; –CH ), 3.252 (s, 2H; –CH ),
2
(–CH bend), 1498 (C=C str), 1336.37 (C–F str), 1275.25
2
2
2
.002 (s, 1H; –NH), 6.889 (s, 1H; Ar–H), 3.735 (s, 6H;
(Aliph C–N str), 927.56 (N–N str), 864.79 (ortho-substi-
-OCH ), 6.178 -6.721 (d, 1H; Ar–H), 6.942 (s, 1H; Ar–H),
3
tution), 510.84 (C–Cl); NMR (CDCl , d, ppm): d = 7.96
3
.937 (s, 1H; Ar–H), 1.318–1.357 (s, 1H; –CH),
.263–0.279 (q, 2H; [CH ]), 0.491–0.529 (q, 2H; [CH] );
(s, 1H; Ar–H), 10.980 (s, 1H; COOH), 3.992 (s, 2H; NH2),
3.530–3.546 (d, 1H; –CH), 3.273–3.298 (d, 1H; –CH),
2.911–3.039 (m, 1H; –CH), 1.086–1.103 (d, 6H; [–CH ] ),
2
2
?
Mass (ESI, m/z): M = 608.194.
5-amino-1-cyclopropyl-7-[(3R,5S)3,5-dimethylpiperazin-
-yl]-6,8-difluoro-4-oxo-quinoline-3-carboxylic acid]-5-
phenyl)-1,3,4 thiadiazole (14a) Pale-yellow needle-
shaped crystals; yield: 47.3 %; m.p.: 330°–336°; IR (KBr,
3
2
3
2
–
.255 (s, 2H; CH ), 8.005 (s, 1H; –NH), 7.417–7.462 (s,
2
[
H; [–CH] ), 7.330 (s, 2H; [–CH] ), 1.318–1.357 (t, 1H;
2
2
1
CH), 0.263–0.279 (q, 2H; [CH ]), 0.491–0.529 (q, 2H;
2
(
?
CH] ); Mass (ESI, m/z): M =643.903.
[
2
-
1
cm ): 3412 & 3189 (–NH bend), 3111.18 (N–H str),
[5-amino-1-cyclopropyl-7-[(3R,5S)3,5-dimethylpiperazin-
1-yl]-6,8-difluoro-4-oxo-quinoline-3-carboxylic acid]-5-
2
3
062.96 (Ar C–H str), 3056.82 (=C–H str), 2234.38 (C–S
1
23

Med Chem Res
Table 1 Antibacterial activity of synthesized compounds (100 lg/mL concentration)
a
Compound
Zone of inhibition in mm ± SD
B. subtillis
S. aureus
E. coli
K. pneumoniae
Control
–
–
–
–
Ciprofloxacin
Sparfloxacin
20.0 ± 0.89
23.0 ± 0.67
8.0 ± 0.05
12.0 ± 0.57
11.0 ± 0.50
10.0 ± 0.05
11.0 ± 0.50
14.0 ± 0.32
16.0 ± 0.76
13.0 ± 0.92
10.0 ± 0.45
8.0 ± 0.55
12.0 ± 0.45
11.0 ± 0.23
10.0 ± 0.89
8.0 ± 0.99
10.0 ± 0.56
9.0 ± 0.78
10.0 ± 0.87
12.0 ± 0.44
21.0 ± 0.87
20.0 ± 0.55
7.0 ± 0.69
7.0 ± 0.76
8.00 ± 0.95
7.0 ± 1.10
8.00 ± 0.98
9.0 ± 0.56
10.0 ± 0.98
10.0 ± 0.94
9.0 ± 0.94
6.0 ± 0.18
9.0 ± 0.65
12.0 ± 0.38
10.0 ± 0.31
9.0 ± 0.67
11.0 ± 0.99
12.0 ± 0.34
9.0 ± 0.54
11.0 ± 0.69
27.0 ± 0.45
29.0 ± 0.29
8.0 ± 0.35
8.0 ± 0.50
9.0 ± 0.32
7.0 ± 0.76
14.0 ± 0.94
17.0 ± 0.76
19.0 ± 0.99
16.0 ± 0.86
10.0 ± 0.97
8.0 ± 0.98
13.0 ± 0.77
10.0 ± 0.59
11.0 ± 0.90
10.0 ± 0.98
24.0 ± 0.44
12.0 ± 0.76
11.0 ± 0.78
11.0 ± 0.45
26.0 ± 0.57
27.0 ± 0.21
6.0 ± 0.50
7.0 ± 0.50
8.0 ± 1.00
6.0 ± 0.76
10.0 ± 0.73
10.0 ± 0.65
11.0 ± 0.76
10.0 ± 0.96
13.0 ± 0.97
7.0 ± 0.99
14.0 ± 0.94
9.0 ± 0.32
11.0 ± 0.21
9.0 ± 0.59
9.0 ± 0.74
11.0 ± 0.66
13.0 ± 0.38
12.0 ± 0.24
7
7
7
7
8
8
8
8
1
1
1
1
1
1
1
1
1
1
a
a
b
c
d
a
b
c
d
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
Mean of three readings
(
3-nitrophenyl)-1,3,4 thiadiazole (14d) Pale-yellow
needle-shaped crystals; yield: 52.7 %; m.p.: 325°–327°; IR
(–CH bend), 1498 (C=C str), 1336.37 (C–F str), 1230.74
2
and 1067.93 (Ar–OCH ) 1275.25 (Aliph C–N str), 927.56
3
-
KBr, cm ): 3412 & 3189 (–NH bend), 3111.18 (N–H
1
(
(N–N str); NMR (CDCl , d, ppm): d = 7.96 (s, 1H; Ar–H),
2
3
str), 3062.96 (Ar C–H str), 3056.82 (=C–H str), 2234.38
C–S str), 1796.38 (C=O str), 1635.64 for C=O, 1522.61
and 1385.17 (–NO ), 1456.26 for ring (Ar–C=O str),
10.980 (s, 1H; COOH), 3.992 (s, 2H; NH ), 3.530–3.546
2
(
(d, 1H; –CH), 3.273–3.298 (d, 1H; –CH), 2.911–3.039 (m,
1H; –CH), 1.086–1.103 (d, 6H; [–CH ] ), 3.255 (s, 2H;
3 2
2
1
412.20 (–CH bend), 1498 (C=C str), 1336.37 (C–F str),
2
CH ), 8.014 (s, 1H; –NH), 6.885 (s, 1H; –CH),
2
1
275.25 (Aliph C–N str), 927.56 (N–N str), 864.79 (ortho-
3.730–3.734 (d, 6H; -[CH ] ), 6.700–6.723 (d, 1H; –CH),
2
3
substitution); NMR (CDCl , d, ppm): d = 7.96 (s, 1H; Ar–
H), 10.980 (s, 1H; COOH), 3.992 (s, 2H; NH2),
6.934 (s, 1H; –CH), 1.318–1.357 (t, 1H; –CH),
0.263–0.279 (q, 2H; [CH ]), 0.491–0.529 (q, 2H; [CH] );
3
2
2
?
Mass (ESI, m/z): M = 669.172.
3
2
3
–
–
–
.530–3.546 (d, 1H; –CH), 3.273–3.298 (d, 1H; –CH),
.911–3.039 (m, 1H; –CH), 1.086–1.103 (d, 6H; [–CH ] ),
3
2
.255 (s, 2H; CH ), 8.014 (s, 1H; –NH), 8.457 (s, 1H;
2
CH), 8.158–8.169 (d, 1H; –CH), 7.542–7.584 (t, 1H;
CH), 7.856–7.871 (d, 1H; –CH), 1.318–1.357 (t, 1H;
Antimicrobial activity
CH), 0.263–0.279 (q, 2H; [CH ]), 0.491–0.529 (q, 2H;
2
All novel synthesized compounds were screened for their
in vitro antibacterial activity against two gram-positive
(Bacillus subtilis [MTCC 121], Staphylococcus aureus
[MTCC 7443]), two gram-negative (Escherichia coli
[MTCC 118], Klebsiella pneumonia [MTCC 7028]) and
antifungal activity against Candida albicans [MTCC 1637]
and Aspergillus tubingensis [MTCC 2479] by paper disk
diffusion method (Aneja 2007). The paper disks which
were previously sterilized by dry heat and impregnated
?
CH] ); Mass (ESI, m/z): M = 654.159.
[
2
5
1
-amino-1-cyclopropyl-7-[(3R,5S)3,5-dimethylpiperazin-
-yl]-6,8-difluoro-4-oxo-quinoline-3-carboxylicacid]5
(
3,4dimethoxyphenyl)thiadiazole (14e) Pale-yellow
needle-shaped crystals; yield: 74.6; m.p.: 340°–342°; IR
-
KBr, cm ): 3111.18 (N–H str), 3062.96 (Ar C–H str),
1
(
3
1
056.82 (=C–H str), 2234.38 (C–S str), 1796.38 (C=O str),
635.64 for C=O, 1456.26 for ring (Ar–C=O str), 1456.20
123

Med Chem Res
Table 2 Antifungal activity of synthesized compounds (100 lg/mL)
was neutralized with liquor ammonia to get cyclized pro-
duct, thiadiazole.
a
Compound
Zone of inhibition in mm ± SD
In second series, different aldehydes reacted with
thiosemicarbazide to yield thiosemicarbazones. It was
cyclized in the presence of ferric chloride to yield thiadi-
azole. Different derivatives of 2-chloro acetyl amino-5-
alkylthiadiazole were simultaneously fused with cipro-
floxacin and sparfloxacin in the presence of dimethylfor-
mamide and sodium bicarbonate. The compounds were
C. albicans
A. tubingensis
Control
–
–
Clotrimazole
18.0 ± 0.57
6 ± 0.29
8 ± 0.32
10 ± 0.53
9 ± 0.59
7 ± 0.07
9 ± 0.24
11 ± 0.68
10 ± 0.31
8 ± 0.38
10 ± 0.57
11 ± 0.43
12 ± 0.96
13 ± 0.53
12 ± 0.20
11 ± 0.36
12 ± 0.95
13 ± 0.36
16 ± 0.85
19.0 ± 0.76
6 ± 0.26
7 ± 0.37
9 ± 0.89
8 ± 0.57
7 ± 0.23
8 ± 0.35
10 ± 0.96
9 ± 0.16
8 ± 0.84
11 ± 0.11
10 ± 0.66
11 ± 0.24
12 ± 0.37
10 ± 0.85
13 ± 0.27
11 ± 0.64
13 ± 0.39
15 ± 0.15
7
7
7
7
8
8
8
8
1
1
1
1
1
1
1
1
1
1
a
a
b
c
1
characterized by spectral data (IR, H NMR and Mass) and
d
evaluated for antimicrobial activity.
a
All synthesized compounds and standard drugs are taken
in the concentration of 100 lg/mL in DMF and screened
for antimicrobial activity. Some of the compounds showed
good activity against gram-positive, gram-negative bacteria
and fungi. The data of antimicrobial studies showed that
compounds 7c and 8c have comparable good antibacterial
activity which may be due to six carbon chains attached to
thiadiazole which may be increasing its lipophilicity
among ciprofloxacin and sparfloxacin derivatives. Com-
pounds 13c and 14b are having good activity and it may be
due to aromatic ring fused with thiadiazole having halogen
substituent.
b
c
d
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
The data of antifungal activity showed that compounds
7c and 8c have good activity among ciprofloxacin and
Mean of three readings
sparfloxacin derivatives, respectively, which may be also
due to higher lipophilicity among all. Compounds 13e and
14e have better activity that may be due to aromatic ring
substitution. So from this study, we can conclude that if the
further clinical studies will be performed and such mole-
cule will be explored, it may lead to give better antimi-
crobial agent where the dose of fluoroquinolones can be
reduced without compromising with the activity of the
parent drug.
with the test compounds (100 lg/mL, Dimethyl formamide
as solvent) were placed on the solidified medium. The
plates were incubated at 37 °C for 24 h. After incubation,
the growth inhibition zones around the disks were
observed, indicating that the examined compound inhibits
the growth of microorganism. Ciprofloxacin and spar-
floxacin in concentration of 100 lg/mL were used as
standard drugs for antibacterial activity, and clotrimazole
in concentration of 100 lg/mL was used as a standard drug
for antifungal activity. Results were interpreted in terms of
the diameter of the zone of inhibition and are given in
Tables 1 and 2.
References
Al-Zoubi LO, Al-Bakri AG, Amawi HA, Al-Balas QA, Alkatheri
AM, Albekairy AM, Qandil AM (2014) Synthesis, antibacterial
evaluation and QSAR of a-substituted-N4-acetamides of cipro-
floxacin and norfloxacin. Antibiotics 3:244–269. doi:10.3390/
antibiotics3030244
Aneja KR (2007) Experiments in microbiology, plant pathology and
biotechnology, 4th edn. New Age International (P) Limited,
Publishers, New Delhi, pp 580–599
Chen CJ, Song BA, Yang S, Xu GF, Bhadury PS, Jin LH, Hu DY, Li
QZ, Liu F, Xue W, Lu P, Chen Z (2007) Synthesis and
antifungal activities of 5-(3,4,5-trimethoxyphenyl)-2-sulfonyl-
1,3,4-thiadiazole and 5-(3,4,5-trimethoxyphenyl)-2-sulfonyl-
Results and discussion
Both the nucleus thiadiazoles and fluoroquinolones are
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