Novel triazole-sulfonamide bearing pyrimidine moieties with carbonic anhydrase inhibitory action: Design, synthesis, computational and enzyme inhibition studies.

A series of new triazole-sulfonamide bearing pyrimidine derivatives were designed and synthesized via click chemistry. All new compounds (SH-1 to SH-28) were validated by 1HNMR, 13CNMR, HRMS, and SH-3 was further structurally validated by X-Ray single diffraction study. These compounds (SH-1 to SH-28) were tested as inhibitors of human carbonic anhydrase (hCA) isoforms, such as hCA I, II, IX and XII, using a stopped flow CO2 hydrase assay. Most of the compounds exhibited significant inhibitory activity against hCA II and weak inhibitory activity against hCA I. The target compounds also displayed moderate to excellent inhibitory activity against tumor-related hCAs IX and XII. Some compounds, e.g., SH-20 (Ki = 9.4 nM), SH-26 (Ki = 1.8 nM) and SH-28 (Ki = 0.82 nM) exhibited excellent inhibitory activity and selectivity profile against hCAs XII over IX. SH-23 displayed promising inhibitory activity and selectivity profile against both tumor-related hCAs IX (Ki = 2.9 nM) as well as XII (Ki = 0.82 nM) over hCA I and II. To understand the molecular interactions, molecular docking study of compounds SH-20, SH-23, SH-26 and SH-28 with hCA XII and SH-23 also with hCA IX were performed. The computational study evidenced favorable interaction between the inhibitors and active residues of both proteins. Some of these derivatives are promising leads for the development of selective, anticancer agents based on CA inhibitors.