Novel benzoyl thioureido benzene sulfonamides as highly potent and selective inhibitors of carbonic anhydrase IX: optimization and bioactive studies

Li Liu; Wanqi Wang; Jin Huang; Zhenjiang Zhao; Honglin Li; Yufang Xu

doi:10.1039/c8md00392k

Novel benzoyl thioureido benzene sulfonamides as highly potent and selective inhibitors of carbonic anhydrase IX: optimization and bioactive studies

Medchemcomm. 2018 Nov 9;9(12):2100-2105. doi: 10.1039/c8md00392k. eCollection 2018 Dec 1.

Authors

Li Liu¹, Wanqi Wang¹, Jin Huang², Zhenjiang Zhao², Honglin Li², Yufang Xu¹

Affiliations

¹ State Key Laboratory of Bioreactor Engineering , Shanghai Key Laboratory of Chemical Biology , East China University of Science and Technology , Shanghai 200237 , China . Email: yfxu@ecust.edu.cn.
² Shanghai Key Laboratory of New Drug Design , School of Pharmacy , East China University of Science and Technology , 130 Mei Long Road , Shanghai 200237 , China . Email: hlli@ecust.edu.cn ; Tel: +86 21 64251399.

Abstract

CA IX has attracted much attention as a promising target for the development of new anticancer agents. In this study, a series of sulfonamide derivatives were designed and synthesized as potential CA IX inhibitors from a lead compound (benzoyl thioureido benzene sulfonamide) discovered by virtual screening. The bioassay demonstrated that some of the synthesized compounds exhibited potent inhibitory activity against CA IX in the subnanomolar range and high selectivity over isozymes CA I and CA II. Among them, compound 6a displayed inhibitory activity against CA IX with an IC₅₀ value of 0.48 nM and about 1500-fold selectivity over CA II. The structure-activity relationship and CA IX selectivity of the new sulfonamide derivatives were also analyzed by molecular docking.