Synthesis and Antitumor Activity of C-3 Arylidene-Substituted Ofloxacin Unsaturated Ketone Derivatives
ZHANG Hui-li1, CUI Hong-yan2*, LI Ke1, HUANG Wen-long3, HU Guo-qiang1*
1. Henan Engineering Technology Research Center of Water Environment and Health, Zhengzhou University of Industrial Technology, Zhengzhou 451150, China; 2. School of Clinical Medicine, Henan University, Kaifeng 475001, China; 3. Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China
Abstract：OBJECTIVE To further optimize the bioisostere of the C-3 carboxylic group for improving antitumor activity of fluoroquinolones. METHODS A fragment or pharmacophore skeleton hopping-based drug molecular design, the title fluoroquinolone unsaturated ketones (3a-3l) were designed and synthesized with an arylidene group both as an isostere of the C-3 carboxylic group and as a fragment of α,β-unsaturated ketone from ofloxacin (1). The structures of title compounds were characterized by spectral data and elemental analysis, and the in vitro antitumor activity against the three tested tumor cell lines was evaluated by a MTT assay. RESULTS Twelve new title compounds were synthesized, and exhibited more potent than parent 1, especially the chlorophenyl compound showed a comparable activity to comparison doxorubicin against Capan-1 cell lines. CONCLUSION A arylidene group as an isostere of the C-3 carboxylic acid group is beneficial to improve antitumor activity, and it further suggests that an α,β-unsaturated ketone skeleton appears to be a promising pharmacophore for further design of lead antitumor fluoroquinolone.
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2021, Vol. 56 
