Design and Synthesis of 3-(Phenylsulfonamido)benzamide Derivatives as Potent Carbonic Anhydrase IX Inhibitors: Biological Evaluations and Molecular Modeling Studies.

Abstract

Introduction: Carbonic anhydrase IX (CAIX) is known to be overexpressed in various tumors and plays a significant role in tumor development and progression.

Methods: A series of 3-(benzylsulfonamido)benzamides derivatives was synthesized and tested for their CAIX inhibitory activities. The two most active compounds were subjected to cytotoxicity testing against a panel of 60 cancer cell lines.

Results: Many of the synthesized compounds successfully inhibited CAIX activities, exhibiting IC₅₀ values in the low nanomolar range. The most potent CAIX inhibitor was compound 14, with an IC₅₀ of 140 nM. Structure-activity relationship analysis of the synthesized compounds supported with molecular docking revealed strong coordination of sulfonamide moiety with the catalytic Zn²⁺ metal, hydrophobic interactions of the benzylsulfonamido ring with a hydrophobic pocket, and π- stacking interactions of the aryl ring with an aromatic surface. The two most active analogues (10 and 14) were further tested for their antiproliferative activities in the NCI-60 human tumor cell lines. Notably, compound 14 demonstrated potent growth inhibitory effects against several cancer cell lines.

Conclusion: The synthesized analogues represent a novel scaffold for the treatment of different types of cancer by targeting CAIX.