In‐vitro and in‐silico investigations of SLC‐0111 hydrazinyl analogs as human carbonic anhydrase I, II, IX, and XII inhibitors

Two novel series of hydrazinyl‐based benzenesulfonamides 9a–j and 10a–j were designed and synthesized using SLC‐0111 as the lead molecule. The newly synthesized compounds were evaluated for their inhibitory activity against four different human carbonic anhydrase (hCA) isoforms I, II, IX, and XII. Both the series reported here were practically inactive against the off‐target isozyme hCA I. Notably, derivative 10a exhibited superior potency (K_i of 10.2 nM) than acetazolamide (AAZ) against the cytosolic isoform hCA II. The hCA IX and XII isoforms implicated in tumor progression were effectively inhibited with K_is in the low nanomolar range of 20.5–176.6 nM and 6.0–127.5 nM, respectively. Compound 9g emerged as the most potent and selective hCA IX and XII inhibitor with K_i of 20.5 nM and S_I of 200.1, and K_i of 6.0 nM and S_I of 683.7, respectively, over hCA I. Furthermore, six compounds (9a, 9h, 10a, 10g, 10i, and 10j) exhibited significant inhibition toward hCA IX (K_is = 27.0, 41.1, 27.4, 25.9, 40.7, and 30.8 nM) relative to AAZ and SLC‐0111 (K_is = 25.0 and 45.0 nM, respectively). These findings underscore the potential of these derivatives as potent and selective inhibitors of hCA IX and XII over the off‐target hCA I and II.