Design, synthesis and in silico insights of novel 1,2,3-triazole benzenesulfonamide derivatives as potential carbonic anhydrase IX and XII inhibitors with promising anticancer activity

Abstract

Novel 1,2,3-triazole benzenesulfonamide derivatives were designed as inhibitors for the tumor- related hCA IX and XII isoforms. Most of the synthesized compounds showed good inhibitory activity against hCA IX and hCA XII isoforms. Compounds 4d, 5h and 6b, exhibited remarkable activity as hCA IX inhibitors, with K_i values in the range of 0.03 to 0.06 µM, more potent than AAZ. Additionally, compounds 5b and 6d, efficiently inhibited hCA XII isoform, with K_i value of 0.02 µM, respectively, similar to AAZ. Further investigation for those potent derivatives against MCF-7, Hep-3B and WI-38 cell lines was achieved. Compounds 4d and 6d exerted dual cytotoxic activity against MCF-7 and Hep-3B cell lines, with IC₅₀ values of 3.35 & 2.12 µM against MCF-7 cell line and 1.72 & 1.56 µM against Hep-3B cell line, with high SI values ranged from 8.92 to 17.38 on both of the cell lines. Besides, they showed a high safety profile against normal human cell line, WI-38. Moreover, compound 5h had better cytotoxic effect on MCF-7 than the reference, DOX, with IC₅₀ value of 4.02 µM. While, compounds 5b and 6b showed higher activity against Hep-3B if compared to the reference drug, 5-FU. From ADME study, compounds 4d, 5b, 6b and 6d obeyed Lipinski's rule of five, and they might be orally active derivatives, while, compound 5h exerted less oral bioavailability than the reference standard acetazolamide. Molecular docking and MDS studies predicted the binding mode and the stability of the target compounds inside hCA IX and hCA XII active sites, especially for compounds 5b and 6b.

Keywords: Carbonic anhydrase inhibitors; Cytotoxic activity; Molecular dynamic simulations; Triazole benzenesulfonamides.