Design and synthesis of 3-(azepan-1-ylsulfonyl)-N-aryl benzamide derivatives as potent carbonic anhydrase IX inhibitors with anticancer activities.

Authors

Mohammad A Khanfar, Mohammad Saleh

Published in

Zeitschrift fur Naturforschung. C, Journal of biosciences. Mar 03, 2025. Epub Mar 03, 2025.

Abstract

Carbonic anhydrase IX (CAIX) is known to be overexpressed in various tumors and plays a significant role in tumor development and progression. A series of 3-sulfonamide benzoate derivatives with a 7-membered azepane ring were synthesized and evaluated for their CAIX inhibitory activities. Most of the synthesized compounds successfully inhibited CAIX activities, exhibiting IC₅₀ values in the low nanomolar range. The most potent CAIX inhibitor was compound 26, with an IC₅₀ of 19 nM. A structure-activity relationship analysis of the synthesized compounds was conducted, and molecular docking revealed strong coordination with the catalytic Zn²⁺ metal, hydrophobic interactions of the azepane ring with a hydrophobic pocket, and π-stacking interactions of the aryl ring with an aromatic surface. The three most active analogues (8, 16, and 26) were further tested for their antiproliferative activities in the NCI-60 human tumor cell lines screen. Notably, compound 16 (CAIX, IC₅₀ = 310 nM) demonstrated potent growth inhibitory effects against several cancer cell lines.

PMID:
40019870
Bibliographic data and abstract were imported from PubMed on 01 Mar 2025.

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