Synthesis and antiproliferative activity of 1-[(sub)]-6-fluoro-3-[(sub)]-1, 3,4-oxadiazol-2-yl-7-piperazino-1, 4-dihydro-4-quinolinone derivatives

Article abstract of DOI:10.1007/s00044-007-9031-x

A series of 1-[(sub)]-6-fluoro-3- [(sub)]-1, 3, 4-oxadiazol-2-yl-7- piperazino-1, 4-dihydro 4-quinolinones were synthesized by the reaction between ciprofloxacin and norfloxacin with an appropriate acid hydrazide in phosphorous oxychloride. All newly synthesized compounds were evaluated for their antiproliferative activities against human lung tumor cell lines (A 549). Fluoroquinolone with oxadiazole (Q ₂ ) 1-cyclopropyl-6-fluoro-3- [5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl]-7-piperazino-1, 4-dihydro-4-quinolinone was found to be the most active compound in vitro with a half-maximal inhibitory concentration (IC₅₀) of 9.0 μg/mL.

Full text of DOI:10.1007/s00044-007-9031-x

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2007) 16:292–299
DOI 10.1007/s00044-007-9031-x
ORIGINAL RESEARCH
Synthesis and antiproliferative activity of 1-[(sub)]-6-
fluoro-3-[(sub)]-1, 3,4-oxadiazol-2-yl-7-piperazino-1,
4-dihydro-4-quinolinone derivatives
Mohammad Shaharyar Æ Mohamed Ashraf Ali Æ
Mohammad Mustaqeem Abdullah
Received: 24 February 2007 / Accepted: 4 September 2007 / Published online: 23 October 2007
¨
ꢀ Birkhauser Boston 2007
Abstract A series of 1-[(sub)]-6-fluoro-3- [(sub)]-1, 3, 4-oxadiazol-2-yl-7-pipe-
razino-1, 4-dihydro 4-quinolinones were synthesized by the reaction between
ciprofloxacin and norfloxacin with an appropriate acid hydrazide in phosphorous
oxychloride. All newly synthesized compounds were evaluated for their antiprolif-
erative activities against human lung tumor cell lines (A 549). Fluoroquinolone with
oxadiazole (Q2) 1-cyclopropyl-6-fluoro-3- [5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl]-
7-piperazino-1, 4-dihydro-4-quinolinone was found to be the most active compound
in vitro with a half-maximal inhibitory concentration (IC50) of 9.0 lg/mL.
Keywords Quinolone Á Oxadiazole Á Human lung tumor cell lines Á
A 549
Introduction
Cancer is one of the major diseases of the present world, with one in four persons in
developed countries expected to get cancer in their lifetime. Of the new cases each
year, more than 50% will occur in developing countries, with six to nine million
new cases occurring in India. Effective treatment of cancer results from the
destruction of the cancer cells, which is a direct result of the cytotoxicity of drugs
against proliferating cells. Most of the clinically available anticancer drugs interfere
with DNA function to exert their cytotoxicity. DNA intercalators represent an
important class of anticancer drugs. Lung cancer is the most frequent cause of
cancer-related deaths and accounts for more than a million deaths yearly worldwide
with non-small-cell lung cancer (NSCLC) accounting for 75–85% of lung cancer.
M. Shaharyar (&) Á M. A. Ali Á M. M. Abdullah
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Jamia Hamdard University,
Hamdard Nagar, New Delhi 110062, India
e-mail: yarmsy@rediffmail.com

Med Chem Res (2007) 16:292–299
293
The pathogenesis of lung cancer involves the accumulation of multiple molecular
abnormalities, particularly as a result of exposure to smoking. These alterations
include genetic mutations, chromosomal changes with subsequent inactivation of
tumor suppressor genes, and the overactivity of signal-transduction cascades.
Apoptosis (programmed cell death) not only occurs naturally during development
and differentiation, but also acts to eliminate damaged cells after injury (Evans,
1993). Molecular studies of lung cancer have provided new avenues for early
diagnosis and therapeutic strategies. However, certain patients are still plagued by
rapid disease recurrence and progression, and there has been no significant
improvement in their overall survival. Therefore, it remains a disease with poor
prognosis and the primary cause of cancer-related death in both men and women
despite recent advances in drug development. The development or presence of
resistance to chemotherapeutic agents is a major obstacle to the effective treatment
of lung cancer. Identifying the molecular determinants of sensitivity and resistance
to chemotherapy is expected to improve therapeutic efficacy. Several fluoroquino-
lone derivatives have been examined as antibacterial (Pottumarthy, 2006),
antimycobacterial (Gillespie et al., 2005; Zhao, 2005; Kawahara, 2001;Vacher,
1999; Saito, 1994; Kamal, 2005), antiviral (Witvrouw, 1998; Denizot and Lang,
1986), and anticancer (Wang, 2002; Shammas et al., 2003; Kim et al., 2003; Chu
et al., 1992; Permana et al., 1994) agents. The current work describes the synthesis
of a novel fluoroquinolone-substituted oxadiazole moiety with encouraging
antiproliferative activity against human lung tumor cell lines (A 549).
Results and discussion
Chemistry
The synthesis of fluoroquinolone-substituted oxadiazole derivatives was carried out
following the steps shown in Schemes 1 and 2. The compounds Q1–Q7 and Q8–Q14
were synthesized by reacting ciprofloxacin and norfloxacin with the appropriate acid
hydrazide in glacial acetic acid for 4–8 hours, resulting in a 65–91% yield after
recrystallization with a mixture of ethanol and dimethyl formamide (DMF). The
purity of the compounds was checked by thin-layer chromatography (TLC) using
various mobile bases and elemental analyses. Both analytical and spectral data [1H-
nuclear magnetic resonance (NMR), infrared (IR)] of all the synthesized compounds
were in full agreement with the proposed structures. In general, IR spectra revealed
a C–O–C peak at 1150 cm–1, a C=N peak at 1600 cm–1, and an NH peak at 3300
1
cm–1. In the H-NMR the signals of the respective protons of the prepared titled
compounds were verified on the basis of their chemical shifts, multiplicities, and
coupling constants. The spectra showed a multiplet at d 0.69–1.23 ppm
corresponding to cyclopropyl protons, a singlet at d 2.3 ppm corresponding to the
cyclopropyl CH proton, a multiplet at d 2.4–3.2 corresponding to piperazine
protons, a multiplet at d 7.25–8.49 corresponding to aromatic protons, a quartet at d
4.13 ppm corresponding to the CH2 protons, a triplet at d 1.19 ppm corresponding to
the CH3 group, and a singlet at d 4.02 ppm for the NH proton.

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Med Chem Res (2007) 16:292–299
Antiproliferative activity
The synthesized compounds Q1–Q7 and Q8–Q14 were tested for their antiprolif-
erative activity against in vitro human lung tumor cell lines (A 549) using the
MTT assay system (Saito, 1994; Kim et al., 2003). The resulting IC50 values of
cancer cell-growth inhibition by the fused novel fluroquinolone analogues are
summarized in Table 1. Among the newly synthesized compounds, electron-rich
group substituted analogue 1-cyclopropyl-6-fluoro-3-[5-(4-nitrophenyl)-1,3,4-oxa-
diazol-2-yl]-7-piperazino-1,4-dihydro-4-quinolinone (Q2) showed potent inhibitory
activities with an IC50 value of 9.0 lg/mL. Next in the order 1-cyclopropyl-6-
fluoro-3-[5-(2-naphthyloxymethyl)-1,3,4-oxadiazol-2-yl]-7-piperazino-1,4-dihydro-
4-quinolinone (Q4) showed good inhibitory activity against human lung tumor cell
lines (A 549), with an IC50 value of 16.0 lg/mL. However, N1-phenyl phenoxy
methyl-substituted fused ciprofloxacin-substituted oxadiazole resulted in moderate
activity. On the other hand, norfloxacin-substituted oxadiazole derivatives showed
slight to moderate activity against human lung tumor cell lines (A 549). 1-
Napthoxymethyl phenyl methyl-substituted oxadiazole derivatives of both fluor-
oquinolone derivatives resulted in a decrease in the inhibitory activity. These
reports clearly showed that the presence of C-3 ciprofloxacin-substituted 1,3,4
oxadiazole produced more inhibitory activity than C-3 norfloxacin substituted
oxadiazole analogues. Finally C-3 ciprofloxacin with C-5 4-nitro phenyl groups at
the 1,3,4 oxadiazole nucleus caused remarkable improvement in antiproliferative
activity.
Conclusion
Among the newer derivatives, 1-cyclopropyl-6-fluoro-3- [5-(4-nitrophenyl)-1,3,4-
oxadiazol-2-yl]-7-piperazino-1,4-dihydro-4-quinolinone (compound Q2) showed
promising activity and the remaining showed moderate to good activity against
human lung tumor cell lines (A 549). It is conceivable that derivatives showing
antiproliferative activity can be further modified to exhibit better anticancer
chemotherapeutic agents. Further studies to acquire more information about QSAR
are in progress.
POCl
H SO
3
2
4
NH NH H O
2
2
2
+
R CONHNH
1
R COOH
R COOC H
1 2 5
C H OH
2
1
2
5
Ciprofloxacin
C H OH
2
5
HN
N
F
N
O
R1
O
N
N
Q1-Q7
R =C H , 4-NO -C H ,C H -NH-C H , 2-C H OCH , 1-C H OCH ,C H CH ,C H OCH
2
1
6
5
2
6
4
6
5
6
4
10
7
2
10
7
2
6
5
2
6
5
Scheme 1 Protocol for the synthesis 1-[(cyclopropyl)]-6-fluoro-3- [5-(sub)]-1, 3,4-oxadiazol-2-yl)-7-
piperazino-1, 4-dihydro 4-quinolinone

Med Chem Res (2007) 16:292–299
295
POCl
H SO
3
2
4
NH NH H O
2
2 2
+
R CONHNH
R COOH
R COOC H
1 2 5
C H OH
1
2
1
2
5
Norfloxacin
C H OH
2
5
CH3
HN
N
F
N
O
R1
O
N
N
Q8-Q14
R =C H , 4-NO -C H ,C H -NH-C H , 2-C H OCH , 1-C H OCH ,C H CH ,C H OCH
2
1
6
5
2
6
4
6
5
6
4
10
7
2
10
7
2
6
5
2
6
5
Scheme 2 Protocol for the synthesis 1-[(ethyl)]-6-fluoro-3- [5-(sub)]-1, 3,4-oxadiazol-2-yl)-7-
piperazino-1, 4-dihydro 4-quinolinone
Table 1 Physical constants and antiproliferative activity of the synthesized compounds
CH3
HN
HN
N
F
N
N
F
N
O
O
O
R1
R1
O
N
N
N
N
Q1-Q7
Q8-Q14
Compound
R1
Yield (%) MP (ꢁC) Molecular formula Molecular weight aIC50
Q1
C6H5
4-NO2–C6H4
65
69
220
218
208
235
260
233
219
229
263
237
283
276
212
229
-
C24H22N5O2F
C24H21N6O4F
C30H27N6O2F
C29H26N5O3F
C29H26N5O3F
C25H24N5O2F
C25H24N5O3F
C23H22N5O2F
C23H21N6O4F
C29H27N6O2F
C28H26N5O3F
C28H26N5O3F
C24H24N5O2F
C24H24N5O3F
-
431.46
476.46
522.58
511.55
511.55
445.49
461.49
419.45
464.45
510.56
499.54
499.54
433.48
449.48
-
46.0
8.0
Q2
Q3
C6H5–NH–C6H4 74
b–C10H7–O–CH2 69
a–C10H7–O–CH2 82
52.0
16.0
96.2
86.0
48.6
112.0
74.3
88.6
80.2
126.8
118.4
76.8
35
Q4
Q5
Q6
C6H5CH2
C6H5OCH2
C6H5
91
80
62
76
Q7
Q8
Q9
4-NO2–C6H4
Q10
Q11
Q12
Q13
Q14
C6H5–NH–C6H4 83
b-C10H7–O–CH2 91
a-C10H7–O–CH2 73
C6H5CH2
C6H5OCH2
-
67
85
-
Dacarbazine
a
Human lung tumor cell lines (A 549)

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Med Chem Res (2007) 16:292–299
Experimental
All chemicals were supplied by Merck (Germany) and S.D Fine Chemicals (India).
Melting points were determined by the open-tube capillary method and are
uncorrected. The purity of the compounds was checked on thin-layer chromatography
(TLC) plates (silica gel G) in the solvent system toluene-ethyl formate-formic acid
(5:4:1) and benzene-methanol (8:2), the spots were located under iodine vapors or
ultraviolet (UV) light. IR spectra were obtained on a Perkin-Elmer 1720 FT-IR
spectrometer (KBr Pellets). 1H-NMR spectra were recorded on a Bruker AC 300 MHz
spectrometer using trimethylsilane (TMS) as internal standard in dimethyl sulfoxide
(DMSO)/CDCl3. Mass spectra were recorded on a Bruker Esquire liquid chromatog-
raphy/mass spectroscopy (LC/MS) system using electrospray ionization (ESI), and
elemental analyses were performed on a Carlo Erba 1106 elemental analyzer.
General procedure for synthesis of compound (Q1–Q7)
The appropriate acid hydrazide (0.01 mole) and ciprofloxacin (0.01 mole) in
phosphorous oxychloride (5 mL) were refluxed for 8–10 hours. The content was
cooled and poured onto crushed ice, made alkaline by sodium carbonate solution
(5%) and the resulting solid was filtered, dried, and recrystallized from a mixture of
ethanol and DMF (Q1–Q7).
(Q1 ) IR: (KBr) cm–1: 697 (C–F), 1150 (C–O–C), 1600 (C=N), 3300 (NH);
1H NMR (DMSO-d6 ppm): 0.79–1.23 (4H,m, cyclopropyl CH2), 2.2 (1H, s,
cyclopropyl CH),4.01(1H, s, NH), 2.4–3.1 (8H,m, piperazine), 6.5–7.36 (3H, m,
quinolone),7.25–7.98 (5H,m,Ar): EISMS: m/z: 432 (M+1); Ana. C24H22N5O2F (C,
H, N).
(Q2 ) IR: (KBr) cm–1: 697 (C–F), 1150 (C–O–C), 1338 (NO2), 1600 (C=N), 3310
(NH);
1H NMR (DMSO-d6 ppm): 0.89–1.23 (4H, m, cyclopropyl CH2), 2.2 (1H, s,
cyclopropyl CH),4.03 (1H, s, NH), 2.4–3.1 (8H,m, piperazine) , 6.5–7.36 (3H, m,
quinolone),7.15–8.42 (4H, m, 4-NO2–Ar): EISMS: m/z: 477(M+1); Ana.
C24H21N6O5F (C, H, N).
(Q3) IR: (KBr) cm–1: 691 (C–F), 1155 (C–O–C), 1600 (C=N), 3300 (NH);
1H NMR (DMSO-d6 ppm): 0.99–1.23 (4H, m, cyclopropyl CH2), 2.2 (1H, s,
cyclopropyl CH), 2.4–3.1 (8H, m, piperazine), 4.6 (2H, s, NH·2), 6.5–7.36(3H, m,
quinolone), 7.45–8.00 (9H, m, Ar): EISMS: m/z 522(M+); Ana. C30H27N6O2F (C,
H, N).
(Q4 ) IR: (KBr) cm–1: 687 (C–F), 1156 (C–O–C), 1600 (C=N), 3300 (NH);
1H –NMR (DMSO-d6 ppm): 1.00–1.23 (4H, m, cyclopropyl CH2), 2.2 (1H, s,
cyclopropyl CH), 2.4–3.1 (8H, m, piperazine), 4.04 (1H, s, NH), 5.02–5.04 (2H, m,
OCH2), 6.5–7.36 (3H, m, quinolone), 8.10–8.22 (7H, m, Ar),: EISMS:
m/z512(M+1); Ana. C29H26N5O3F (C, H, N).
(Q5) IR: (KBr) cm–1: 697 (C–F), 1150 (C–O–C), 1600 (C=N), 3300 (NH);
1H –NMR (DMSO-d6 ppm): 0.69–1.23 (4H,m, cyclopropyl CH2), 2.3(1H, s,
cyclopropyl CH), 2.5–3.3 (8H, m, piperazine), 4.03 (1H, s, NH), 5.04–5.06(2H, m,

Med Chem Res (2007) 16:292–299
297
OCH2), 6.5–7.36(3H, m, quinolone), 7.88–8.12 (7H, m, Ar),: EISMS:
m/z512(M+1); Ana. C29H26N5O3F (C, H, N).
(Q6) IR: (KBr) cm–1: 697 (C–F), 1110 (C–O–C), 1600 (C=N), 3320 (NH);
1H NMR (DMSO-d6 ppm): 0.79–1.23 (4H,m, cyclopropyl CH2), 2.2 (1H, s,
cyclopropyl CH), 2.6–3.4 (8H, m, piperazine), 3.90–4.00 (2H, m, CH2), 4.04 (1H, s,
NH), 6.5–7.36(3H, m, quinolone), 7.96–8.18 (5H, m,Ar): EISMS: m/z 445 (M+1);
Ana. C25H24N5O2F (C, H, N).
(Q7) IR: (KBr) cm–1: 697 (C–F), 1150 (C–O–C), 1600 (C=N), 3300 (NH);
1H NMR (DMSO-d6 ppm): 0.99–1.23 (4H, m, cyclopropyl CH2), 2.3 (1H, s,
cyclopropyl CH), 2.4–3.3 (8H, m, piperazine), 4.02(1H, s, NH), 5.02–5.04 (2H, m,
OCH2), 6.5–7.36 (3H, m, quinolone), 8.15–8.14 (5H, m, Ar),: EISMS: m/z 462
(M+1); Ana. C25H24N5O3F (C, H, N).
General procedure for synthesis of compound (Q8–Q14)
The appropriate acid hydrazide (0.01 mole) and norfloxacin (0.01 mole) in
phosphorous oxychloride (5 mL) was refluxed for 8–10 hrs. The content was cooled
and poured onto crushed ice, made alkaline by sodium carbonate solution (5%) and
the resulting solid was filtered, dried, and recrystalized from a mixture of ethanol
and DMF(Q8–Q14).
(Q8 ) IR: (KBr) cm–1: 697 (C–F), 1150 (C–O–C), 1600 (C=N), 3300 (NH);
1H NMR (DMSO-d6 ppm): 1.19–1.22 (3H, t, CH3), 2.4–3.25 (8H, m, piperazine),
4.04 (1H, s, NH), 4.13–4.19 (2H, q, CH2), 6.5–7.36 (3H, m, quinolone), 7.47–8.09
(5H, m, Ar): EISMS: m/z: 420(M+1); Ana. C23H22N5O2F (C, H, N).
(Q9) IR: (KBr) cm–1: 697 (C–F), 1150 (C–O–C), 1338 (NO2), 1600 (C=N), 3300
(NH);
1H NMR (DMSO-d6 ppm): 1.19–1.22 (3H, t, CH3), 2.4–3.25 (8H, m,
piperazine),4.03 (1H, s, NH), 4.13–4.19 (2H, q, CH2), 6.5–7.36 (3H, m,
quinolone),7.47–8.49 (4H, m, Ar): EISMS: m/z: 465(M+1); Ana. C23H21N6O4F
(C, H, N).
(Q10) IR: (KBr) cm–1: 697 (C–F), 1150 (C–O–C), 1600 (C=N), 3300 (NH);
1H –NMR (DMSO-d6 ppm): 1.19–1.22 (3H, t, CH3), 2.4–3.25 (8H, m,
piperazine), 4.13–4.19 (2H, q, CH2), 4.61 (2H, s, NH·2), 6.5–7.36(3H, m,
quinolone), 7.47–8.09 (9H, m, Ar): EISMS: m/z: 512 (M+1); Ana. C29H27N6O2F (C,
H, N).
(Q11) IR: (KBr) cm–1: 697 (C–F), 1160 (C–O–C), 1600 (C=N), 3300 (NH);
1H NMR (DMSO-d6 ppm): 1.19–1.22 (3H, t, CH3), 2.4–3.25 (8H, m, piperazine),
4.03 (1H, s, NH), 4.13–4.19 (2H, q, CH2), 5.01–5.03(2H, m, OCH2), 6.5–7.36 (3H,
m, quinolone), 7.47–8.09 (7H, m, Ar): EISMS: m/z: 500 (M+1); Ana. C28H26N5O3F
(C, H, N).
(Q12) IR: (KBr) cm–1: 697 (C–F), 1150 (C–O–C), 1600 (C=N), 3300 (NH);
1H NMR (DMSO-d6 ppm): 1.19–1.22 (3H, t, CH3), 2.4–3.25 (8H, m, piperazine),
4.04 (1H, s, NH), 4.13–4.19 (2H, q, CH2), 5.01–5.03(2H, m, OCH2), 6.5–7.36 (3H,
m, quinolone), 7.27–7.79 (7H, m, Ar): EISMS: m/z: 500 (M+1); Ana. C28H26N5O3F
(C, H, N).

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Med Chem Res (2007) 16:292–299
(Q13) IR: (KBr) cm–1: 692 (C–F), 1152 (C–O–C), 1620 (C=N), 3320 (NH);
1H NMR (DMSO-d6 ppm): 1.19–1.22 (3H,t,CH3), 2.3–3.25 (8H, m, piperazine),
3.90–4.00 (2H, m, CH2), 4.03 (1H, s, NH), 4.13–4.19 (2H q, CH2), 6.47–7.29 (5H,
m, Ar), 6.5–7.36 (3H, m, quinolone): EISMS: m/z: 433 (M+); Ana. C24H24N5O2F
(C, H, N).
(Q14) IR: (KBr) cm–1: 687 (C–F), 1160 (C–O–C), 1610 (C=N), 3310 (NH);
1H NMR (DMSO-d6 ppm): 1.19–1.22 (3H,t,CH3), 2.6–3.25 (8H, m, pipera-
zine),4.04 (1H, s, NH), 4.13–4.19 (2H, q, CH2), 5.02–5.04 (2H, m,OCH2), 6.47–
7.09 (5H, m, Ar), 6.5–7.36(3H, m, quinolone): EISMS: m/z: 449 (M+); Ana.
C24H24N5O3F (C, H, N).
Cytotoxic assay
The cytotoxicity assay was carried out using 0.1 mL of cell suspension containing
10,000 cells, which was seeded in each well of a 96 well microtiter plate (Nunc and
Tarsons). Fresh medium containing different concentration of the extracts was
added 24 hours after seeding. Control cells were incubated without the test extracts
and with DMSO (solvent). The very small percentage of DMSO present in the wells
(maximum 0.2%) did not affect the experimental results. The microtiter plates were
incubated at 37ꢁC in a humidified incubator with 5% CO2 for a period of three days.
Twelve wells were used for each concentration of the extracts. Morphological
changes were examined using an inverted microscope. The cells were observed at
different time intervals during the incubation period in the presence or absence of
the compound. Cellular viability was determined by using the standard MTT [3-
(4,5-dimethylthiozole–2yl)-2,5-diphenyl tetrazolium bromide] assay (Saito, 1994).
MTT assay
The MTT assay is based on the reduction of soluble MTT into a blue–purple
formazan product mainly by mitochondrial reductase activity inside living cells.
The number of viable cells was found to be proportional to the extent of formazan
production for the cell lines used in this study. After incubation, the solutions in four
wells of each concentration were discarded and 50 lL of a solution of 2 mg/mL of
MTT (Sigma Chemicals, St. Louis, MO, USA) in DMEM (without phenol red) was
added and the cultures were incubated for an additional three hours at 37ꢁC. The
supernatant was removed and the cells were treated with propanol (100 lL/well)
and kept aside for 10 minutes at room temperature. The absorbance was read on a
microtiter plate reader (Bio-Rad, Model 550) at a wavelength of 540 nm and the
mean absorbance from four wells was recorded. Mean absorbance taken from cells
grown in the absence of the extracts was taken as 100% cell survival (control).
Acknowledgement The author (M. Shaharyar) thanks the University Grant Commission-New Delhi,
India for a research award, Janab Abdul Mueed for providing the necessary facility, and Dr. Kiran Smith,
National Cancer Institute-USA, for valuable suggestions.

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