Synthesis and antitumor and antibacterial evaluation of fluoro-quinolone derivatives (III): Mono- and bis-Schiff-bases

Article abstract of DOI:10.1016/j.cclet.2012.01.029

To further explore an efficient modified route for the shift from an antibacterial fluoroquinolone to an antitumor one, mono-Schiff bases 6a-6h related to ciprofloxacin C3 carbonylhydrazone and bis-Schiff bases 4a-4h corresponding to C3/C7 carbonylhydrazone/hydrazone attached on a skeleton of ciprofloquinolone were designed and synthesized, and their in vitro antitumor activity against CHO, HL60, L1210 cells and antibacterial activity against Staphylococcus aureus and Escherichia coli were also reported.

Full text of DOI:10.1016/j.cclet.2012.01.029

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 515–517
www.elsevier.com/locate/cclet
Synthesis and antitumor and antibacterial evaluation of
fluoro-quinolone derivatives (III): Mono- and bis-Schiff-bases
a
a
a
a
Guo Qiang Hu a, , Xiao Kui Wu , Guo Qiang Wang , Nan Nan Duan , Xiao Yi Wen ,
*
Tie Yao Cao a, Yin Jun a, Wang Wei a, Song Qiang Xie a, Wen Long Huang b
a Institute of Chemistry & Biology, Henan University, Kaifeng 475001, China
b China Pharmaceutical University, Nanjing 210009, China
Received 16 November 2011
Available online 29 March 2012
Abstract
To further explore an efficient modified route for the shift from an antibacterial fluoroquinolone to an antitumor one, mono-
Schiff bases 6a–6h related to ciprofloxacin C3 carbonylhydrazone and bis-Schiff bases 4a–4h corresponding to C3/C7
carbonylhydrazone/hydrazone attached on a skeleton of ciprofloquinolone were designed and synthesized, and their in vitro
antitumor activity against CHO, HL60, L1210 cells and antibacterial activity against Staphylococcus aureus and Escherichia coli
were also reported.
# 2012 Guo Qiang Hu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Fluoroquinolone; Schiff base; Antitumor evaluation
The discovery of new anticancer lead compounds is an important strategy for further development of new antitumor
drugs to overcome clinically common disadvantages such as a poor selectivity and/or multi-drug resistance in the
treatment of cancers [1]. Simultaneously, a mechanism- or structure-based rational design from currently available
drugs also plays an important role in going to success [2]. Coincidentally, in view of the mechanistic similarities of
targeting topoisomerases as eukaryotic ones, a study on the shift from an antibacterial fluoroquinolone to an antitumor
one has been an important branch in the topoisomerase inhibitors [3]. Moreover, many attempts mainly focused on the
structural changes of current fluoroquinolone drugs related to nitrogen heterocyclic rings attached at the 7-position of
quinoline scaffold [4]. In addition, a few of modifications for the carboxylic group at the 3-position were also
investigated, and it has been proved that it is not necessary for an antitumor fluoroquinolone to remain a carboxylic
group, which could be replaced with a (fused) heterocyclic ring as bioisosterism in our laboratory and others [5].
Unfortunately, it is less known whether a piperazine group at the 7-position should be replaced with an efficient
bioisosterism. So, in order to answer if necessary to remain the piperazine ring for an antitumor fluoroquinolone, we
designed and synthesized two series of mono Schiff-bases 6a–6h related to ciprofloxacin C3 carbonylhydrazone and
bis Schiff-bases 4a–4h corresponding to ciproflo-quinolone C3/C7 carbonylhydrazone/hydrazone with their
antibacterial and antitumor evaluations (Scheme 1).
* Corresponding author.
E-mail addresses: hgqxy@sina.com.cn, hgq@henu.edu.cn (G.Q. Hu).
1001-8417/$ – see front matter # 2012 Guo Qiang Hu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2012.01.029

516
G.Q. Hu et al. / Chinese Chemical Letters 23 (2012) 515–517
Scheme 1. R: H (a); 2-OH (b); 4-CH3O (c); 3, 4-OCH2O (d); 3,4,5-(CH3O)3 (e); 3-OH-4-CH3O (f); 4-F (g); 4-O2N (h).
Precursor ester 1 of ciprofloxacin in refluxing hydrazine hydrate occurred simultaneously a hydrazinolysis of ester
and an nucleophilic substitution of chlorine atom to form 1-cycloproyl-6-fluoro-7-hydrazinoquinolin-4(1H)-one-3-
carboxylic acid hydrazide 2. Similarly, ciprofloxacin in refluxing hydrazine hydrate yielded the corresponding
hydrazide 5 [6]. A condensation of hydrazides 2 and 5 with appropriate aromatic aldehydes 3a–3h gave the title
compounds bis Schiff bases 4a–4h, 3-[(substituted benzylidene hydrazino) carbonyl]-7-(N0-substituted benzylidene
hydrazino)-1-cycloproyl-6-fluoroquinolin-4(1H)-ones, and mono Schiff bases 6a–6h [7], 3-[(substituted benzyl-idene
hydrazino) carbonyl]-1-cycloproyl-6-fluoro-7-piperazin-1-ylquinolin-4(1H)-ones, respectively.
The in vitro antitumor activity for compounds 4a–4h and 6a–6h against CHO (Chinese hamster ovary), HL60
(human leukemia) and L1210 (murine leukemia) cells was evaluated comparison to cirprofloxacin by the standard
MTT assay [5b]. The results demonstrated that both mono- and bis-Schiff bases had an IC50 value within 25.0 mmol
concentration without a significant difference between them, but comparison ciprofloxacin had a poor activity
(IC50 > 150 mmol/L). Meaningfully, the activity of bis Schiff bases 4a–4h against L1210 was obviously better than
mono Schiff bases 6a–6h against CHO. In addition, the in vitro antibacterial activity showed that both mono and bis
Schiff bases had no activity (MIC50 > 64 mg/mL) against Gram-positive bacteria (Staphylococcus aureus
ATCC29213) and Gram-negative bacteria (Escherichia coli ATCC25922) as compared to that of ciprofloxacin
(MIC50 ꢀ 1.0 mg/mL) by the means of double tube dilution method [8]. In conclusion, it is unnecessary for a C3
carboxyl and a C7 piperazine ring in an antitumor fluoroquinolone, an intensive study on structure–activity
relationship (SAR) of antitumor fluoro-quinolones is value for further development.
The structures of the title compounds 4a–4h and representative compounds 4a and 4e were confirmed by their
spectral data [9].
Acknowledgment
This project was supported by the National Natural Science Foundation of China (Nos. 20872028 and 21072045).
References
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[7] J.H. Zheng, M.S. Thesis, Henan University, 2009.
[8] K. ManjunathaK, B. Poojary, P.L. Lobo, et al. J. Med. Chem. 32 (1989) 537.
[9] 3-(Benzylidene hydrazino-carbonyl)-7-(N0-benzylidenehydrazino)-1-cycloproyl-6-fluoroquinolin-4(1H)-one 4a: yield 91%, mp 291–293 8C.
IR (KBr, n): 3447, 1616, 1527, 1433 cmꢁ1; 1H NMR (DMSO-d6) d: 13.26 (s, 1H, CONH), 10.37 (s, 7H, NH), 8.68 (s, 1H, H-2), 8.46 (s, 1H, H-5),
8.40 (brs, 2H, 2ꢂ CH N), 8.20 (s, 1H, H-8), 7.77–7.40 (m, 10H, Ph-H), 3.81–3.84 (m, 1H, H0-1), 1.32–1.20 (m, 4H, H0-2 and H0-3); MS m/z:
Found 468 (M++H), calcd. 467.51 (M+). Anal. for C27H22FN5O2: C 69.37, H 4.74, N 14.98; Found C 69.62, H 4.55, N 15.13. 3-(2-
Hydroxybenzylidene hydrazinocarbonyl)-7-(N0-2-hydroxy benzylidenehydrazino)-1-cycloproyl-6-fluoroquinolin-4(1H)-ones 4b: yield 93%,
mp > 300 8C. IR (KBr, n): 3421, 1655, 1547, 1448 cmꢁ1; 1H NMR (DMSO-d6) d: 13.29 (s, 1H, CONH), 11.34 (s, 7H, NH), 10.40 and 10.32 (2s,
2H, 2ꢂ OH), 8.69 (s, 1H, H-2), 8.57 (s, 1H, H-5), 8.32 (brs, 2H, 2ꢂ CH N), 8.21 (s, 1H, H-8), 7.70–6.94 (m, 8H, Ph-H), 3.82 (m, 1H, H0-1),
1.30–1.15 (m, 4H, H0-2 and H0-3); MS m/z: Found 500 (M++H), calcd. 499.51 (M+). Anal. for C27H22FN5O4: C 64.92, H 4.44, N 14.02; Found C
65.18, H 4.20, N 14.28. 3-(4-Methoxybenzylidenehydrazinocarbonyl)-7-(N0-4-methoxybenzylidene hydrazino)-1-cycloproyl-6-fluoroquinolin-
4(1H)-one 4c: yield 90%, mp 265–267 8C. IR (KBr, n): 3021, 1632, 1544, 1433 cmꢁ1; 1H NMR (DMSO-d6) d: 13.19 (s, 1H, CONH), 10.20 (s,
7H, NH), 8.67 (s, 1H, H-2), 8.58 (s, 1H, H-5), 8.32 (brs, 2H, 2ꢂ CH N), 8.19 (s, 1H, H-8), 7.67–7.04 (m, 8H, Ph-H), 3.36 (m, 1H, H0-1), 1.30–
1.14 (m, 4H, H0-2 and H0-3); MS m/z: Found 528 (M++H), calcd. 527.56 (M+). Anal. for C29H26FN5O4: C 66.03, H 4.97, N 13.27; Found C 66.27,
H 4.74, N 13.52. 3-(3, 4-Methylenedioxybenzylidenehydrazinocarbonyl)-7-(N0-3, 4-methylenedioxybenzylidenehydrazino)-1-cycloproyl-6-
fluoro-quinolin-4(1H)-one 4d: yield 92%, mp > 300 8C. IR (KBr, n): 3086, 1626, 1535, 1449 cmꢁ1 1H NMR (DMSO-d6) d: 13.18 (s, 1H,
;
CONH), 10.22 (s, 7H, NH), 8.74 (s, 1H, H-2), 8.36 (s, 1H, H-5), 8.18 (brs, 2H, 2ꢂ CH N), 8.01 (s, 1H, H-8), 7.36–7.00 (m, 6H, Ph-H), 6.11 (s,
4H, 2ꢂOCH2O), 3.82 (m, 1H, H0-1), 1.31–1.16 (m, 4H, H0-2 and H0-3); MS m/z: Found 556 (M++H), calcd. 555.53 (M+). Anal. for
C
29H22FN5O6: C 62.70, H 3.99, N 12.61; Found C 62.91, H 4.14, N 12.88. 3-(3, 4, 5-Trimethoxybenzylidenehydrazinocarbonyl)-7-(N0-3, 4, 5-
trimethoxybenzylidenehydrazino)-1-cycloproyl-6-fluoroquinolin- 4(1H)-one 4e: yield 84%, mp 272–274 8C. IR (KBr, n): 3073, 1628, 1546,
1447 cmꢁ1; 1H NMR (DMSO-d6) d: 13.16 (s, 1H, CONH), 10.24 (s, 7H, NH), 8.63 (s, 1H, H-2), 8.32 (s, 1H, H-5), 8.16 (brs, 2H, 2ꢂ CH N),
8.04 (s, 1H, H-8), 7.43–7.21 (m, 4H, Ph-H), 3.86 and 3.89 (2s, 18H, 6ꢂ OCH3), 3.80 (m, 1H, H0-1), 1.32–1.18 (m, 4H, H0-2 and H0-3); MS m/z:
Found 648 (M++H), calcd.647.67 (M+). Anal. for C33H34FN5O8: C 61.20, H 5.29, N 10.81; Found C 61.46, H 5.12, N 11.06. 3-(3-Hydroxy-4-
methoxybenzylidenehydrazinocarbonyl)-7-(N0-3-hydroxy-4-methoxybenzylidenehydrazino)-1-cycloproyl- 6-fluoroquinolin-4(1H)-one 4f:
yield 94%, mp > 300 8C. IR (KBr, n): 3365, 1632, 1557, 1448 cmꢁ1 1H NMR (DMSO-d6) d: 13.20 (s, 1H, CONH), 11.22 (s, 7H, NH),
;
9.96 and 10.15 (2s, 2H, 2ꢂ OH), 8.68 (s, 1H, H-2), 8.42 (s, 1H, H-5), 8.17 (brs, 2H, 2ꢂ CH N), 8.05 (s, 1H, H-8), 7.52–7.23 (m, 6H, Ph-H), 3.87
(brs, 6H, 2ꢂ OCH3), 3.82 (m, 1H, H0-1), 1.33–1.20 (m, 4H, H0-2 and H0-3); MS m/z: Found 560 (M++H), calcd. 559.56 (M+). Anal. for
C
29H26FN5O6: C 62.25, H 4.68, N 12.52; Found C 62.51, H 4.46, N 12.80. 3-(4-Fluorobenzylidenehydrazinocarbonyl)-7-(N0-4-fluorobenzy-
lidene hydrazino)-1-cycloproyl-6-fluoroquinolin-4(1H)-one 4g: yield 92%, mp 270–272 8C. IR (KBr, n): 3038, 1630, 1548, 1437 cmꢁ1 1H
;
NMR (DMSO-d6) d: 13.24 (s, 1H, CONH), 11.25 (s, 7H, NH), 8.72 (s, 1H, H-2), 8.51 (s, 1H, H-5), 8.20 (brs, 2H, 2ꢂ CH N), 8.12 (s, 1H, H-8),
7.81–7.53 (m, 8H, Ph-H), 3.85 (m, 1H, H0-1), 1.37–1.22 (m, 4H, H0-2 and H0-3); MS m/z: Found 504 (M++H), calcd.503.49 (M+). Anal. for
C
27H20F3N5O2: C 64.41, H 4.00, N 13.91; Found C 64.68, H 4.13, N 14.12. 3-(4-Nitrobenzylidene hydrazine-carbonyl)-7-(N0-4-nitrobenzy-
lidenehydrazino)-1-cycloproyl-6-fluoroquinolin-4(1H)-one 4h: yield 83%, mp > 300 8C. IR (KBr, n): 3047, 1636, 1555, 1445 cmꢁ1; 1H NMR
(DMSO-d6) d: 13.28 (s, 1H, CONH), 11.26 (s, 7H, NH), 8.68 (s, 1H, H-2), 8.47 (s, 1H, H-5), 8.23 (brs, 2H, 2ꢂ CH N), 8.16 (s, 1H, H-8), 7.83–
7.54 (m, 8H, Ph-H), 3.86 (m, 1H, H0-1), 1.38–1.24 (m, 4H, H0-2 and H0-3); MS m/z: Found 558 (M++H), calcd. 557.50 (M+). Anal. for
C27H20FN7O6: C 58.17, H 3.62, N 17.59; Found C 58.42, H 3.46, N 17.82. 3-(Benzylidenehydrazinocarbonyl)-1-cycloproyl-6-fluoro-7-
piperazin-1-yl-quinolin-4(1H)-one 6a: yield 84%, mp 234–236 8C. IR (KBr, n): 3368, 3038, 1668, 1625, 1473 cmꢁ1; 1H NMR (CDCl3) d: 13.24
(s, 1H, CONH), 8.84 (s, 1H, H-2), 8.21 (s, 1H, CH N), 8.06–7.26 (m, 7H, H-5, H-8 and Ph-H), 3.67 (m, 1H, H0-1), 3.34–2.68 (m, 8H,
piperazine-H), 1.25–1.20 (m, 4H, H0-2 and H0-3); MS m/z: Found 434 (M++H), calcd. 433.49 (M+). Anal. for C24H24FN5O2: C 66.50, H 5.58, N
16.16; Found C 66.76, H 5.38, N 16.44. 3-(3, 4, 5-Trimethoxybenzylidene hydrazinocarbonyl)-1-cycloproyl-6-fluoro-7-piperazin-1-yl-quinolin-
4(1H)-one 6e: yield 80%, mp 251–252 8C. IR (KBr, n): 3446, 2941, 1667, 1626, 1479 cmꢁ1; 1H NMR (CDCl3) d: 13.25 (s, 1H, CONH), 8.77 (s,
1H, H-2), 8.23 (s, 1H, CH N), 8.01 (d, J = 13.2 Hz, H-5), 7.32 (d, J = 7.2 Hz, H-8), 7.15 (s, 2H, Ph-H), 3.89, 3.93 (2s, 9H, 3ꢂ OCH3), 3.56 (m,
1H, H0-1), 3.30–3.15 (m, 8H, piperazine-H), 1.38–1.21 (m, 4H, H0-2 and H0-3); MS m/z: Found 524 (M++H), calcd. 523.57 (M+). Anal. for
C27H30FN5O5: C 61.94, H 5.78, N 13.38; Found C 62.17, H 5.54, N 13.57.