Synthesis and Antitumor Activity of C-3 Arylidene Thiazolotriazolone of Ofloxacin Derivatives
ZHANG Cheng-xia1, ZHANG Hui-li2*, HUANG Wen-long3, HU Guo-qiang1*
1. Institute of Materia Medica, Henan University, Kaifeng 475001, China; 2. School of Pharmacy, Zhengzhou University of Industrial Technology, Zhengzhou 451150, China; 3. Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China
Abstract：OBJECTIVE To discover an efficient strategy for a conversion of the antibacterial activity into an antitumor activity. METHODS Pharmacophore and scaffold hopping-based rational drug design principles, the title fluoroquinolone C-3 thiazolotriazole unsaturated ketones (6a-6l) were designed and synthesized with a S-triazole ring and α,β-unsaturated ketone, respectively, as an isostere and fused modified group from ofloxacin (1), and their structures were characterized by elemental analysis and spectral data, and the in vitro antitumor activity against the tested tumor cell lines was evaluated by a MTT assay. RESULTS Twelve new title compounds were synthesized, and exhibited more significant potency than parent 1. The title compounds with fluorophenyl or O-methoxyphenyl displayed comparable activity to comparasion doxorubicin. CONCLUSION A fused heterocyclic unsaturated ketone skeleton as an isostere of the C-3 carboxylic acid group are shown to be an alternative route for further design of lead antitumor fluoroquinolone.
HU Y, STUMPFE D, BAJORATH J. Recent advances in scaffold hopping [J]. J Med Chem, 2017, 60 (4):1238-1246.
[2]
HU W, HUANG X S, WU J F, et al. Discovery of novel topoisomerase II inhibitors by medicinal chemistry approaches [J]. J Med Chem, 2018, 61 (20):8947-8980.
[3]
GAO L Z, LI T, XIE Y S, et al. Synthesis and antitumor activity of fluoroquinolon-3-yl s-triazole sulfanylacetylhydrazones and s-Triazole hydrazone derivatives (V) [J]. Chin Pharm J (中国药学杂志), 2015, 50 (6):545-549.
[4]
WU S M, YAN Q, NI L L, et al. Synthesis and antitumor activity of fluoroquinolone C-3 fused heterocyclic thiazolo[3,2-b][1,2,4] triazole derivatives (VI) [J]. Chin Pharm J (中国药学杂志), 2016, 51 (5):353-357.
[5]
YANG T, WANG X M, WANG R, et al. Synthesis and antitumor activity evaluation of C-3 (rhodanine unsaturated ketone) amides as ofloxacin derivatives [J]. Chin Pharm J (中国药学杂志), 2017, 52(3):174-177.
[6]
SONG M. Progress in discovery of KIF5B-RET kinase inhibitors for the treatment of non-small-cell lung cancer [J]. J Med Chem, 2015, 58(9):3672-3681.
[7]
ZHUANG C L, ZHANG W, SHENG C Q, et al. Chalcone: a privileged structure in medicinal chemistry[J]. Chem Rev, 2017, 117 (12):7762-7810.
[8]
MAJUMDAR P, PATI A, PATRA M, et al. Acid hydrazides, potent reagents for synthesis of oxygen-, nitrogen-, and/or sulfur-containing heterocyclic rings [J]. Chem Rev, 2014, 114(5):2942-2977.
2020, Vol. 55 
