Synthesis and Antitumor Activity of Rhodanine Methylene-Substituted Levofloxacin Derivatives

doi:10.19894/j.issn.1000-0518.200199

Chinese Journal of Applied Chemistry ›› 2021, Vol. 38 ›› Issue (2): 188-194.DOI: 10.19894/j.issn.1000-0518.200199

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Synthesis and Antitumor Activity of Rhodanine Methylene-Substituted Levofloxacin Derivatives

ZHANG Hui-Li¹, CUI Hong-Yan^2*, HUANG Wen-Long³, HU Guo-Qiang^2*

¹Henan Engineering Technology Research Center of Water Environment and Health, Zhengzhou University of Industrial Technology, Zhengzhou 451150, China
²School of Clinical Medicine, Henan University, Kaifeng 475001, China
³Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China

Received:2020-06-28 Accepted:2020-09-04 Published:2021-02-01 Online:2021-04-10
Supported by:
National Natural Science Foundation of China(Nos.20872028, 21072045)

Abstract

Abstract: To explore an efficient structural modification strategy to enhance the antitumor activity of fluoroquinolones, a methane-rhodanine fragment was used as the bioisosteric replacement of the C-3 carboxylic acid group and consequently twelve new C-3 α,β-unsaturated thiazolone derivatives (6a-6l) were designed and synthesized by Claisen-Schmid condensation reaction with oxazinoquinolin-7-one-6-carbaldehyde (5) derived from levofloxacin (1) and N-substituted rhodanines (2a-2l), respectively. The in vitro antitumor activity of the synthesized compounds is more potent than that of levofloxacin along with lower cytotoxicity against Vero cells. Meanwhile, the structure-activity relationship (SAR) reveals that halophenyl, N-unsubstituted or cyclopropyl rhodaninec ompounds display a better activity than those of the control compounds, especially the IC₅₀ values of cyclopropyl rhodanine compound (6j) against A549 cell growth is comparable to doxorubicin. Thus, an unsaturated ketone annulated rhodanine scaffold as a bioisostere of the C-3 carboxylic acid group is found to be an alternative proposal for improving the antitumor activity of fluoroquinolones. Furthermore, whether an α,β-unsaturated ketone fragment is a promising bioisostere of the C-3 carboxylic acid group is worth further developing.

Key words: Fluoroquinolone, Rhodanine, Unsaturated ketone, Bioisostere, Antitumor activity

CLC Number:

O626.2

ZHANG Hui-Li, CUI Hong-Yan, HUANG Wen-Long, HU Guo-Qiang. Synthesis and Antitumor Activity of Rhodanine Methylene-Substituted Levofloxacin Derivatives[J]. Chinese Journal of Applied Chemistry, 2021, 38(2): 188-194.

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Synthesis and Antitumor Activity of Rhodanine Methylene-Substituted Levofloxacin Derivatives

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