Synthesis of benzamide derivatives with thiourea-substituted benzenesulfonamides as carbonic anhydrase inhibitors

The novel compounds with the chemical structure ofN-({4-[N '-(substituted)sulfamoyl]phenyl}carbamothioyl)benzamide (1a-g) and 4-fluoro-N-({4-[N '-(substituted)sulfamoyl]phenyl}carbamothioyl)benzamide (2a-g) were synthesized as potent and selective human carbonic anhydrase (hCA) I and hCA II candidate inhibitors. The aryl part was changed to sulfacetamide, sulfaguanidine, sulfanilamide, sulfathiazole, sulfadiazine, sulfamerazine, and sulfametazine. TheK(i)values of compounds1a-gwere in the range of 20.73 +/- 4.32 to 59.55 +/- 13.07 nM (hCA I) and 5.69 +/- 0.43 to 44.81 +/- 1.08 nM (hCA II), whereas theK(i)values of compounds2a-gwere in the range of 13.98 +/- 2.57 to 75.74 +/- 13.51 nM (hCA I) and 8.15 +/- 1.5 to 49.86 +/- 6.18 nM (hCA II). Comparing theK(i)values of the final compounds and acetazolamide, compound1cwith the sulfanilamide moiety (K-i = 5.69 +/- 0.43 nM, 8.8 times) and2fwith the sulfamerazine moiety (K-i = 8.15 +/- 1.5 nM, 6.2 times) demonstrated promising and selective inhibitory effects against the hCA II isoenzyme, the main target protein in glaucoma. Furthermore, compounds1d(K-i = 20.73 +/- 4.32, 4 times) and2d(K-i = 13.98 +/- 2.57, 5.9 times), which have the sulfathiazole moiety, were found as potent hCA I inhibitors. Compounds1cand2fcan be considered as the lead compounds determined in the present study, which can be investigated further to alleviate glaucoma symptoms.