Synthesis of benzamide derivatives with thiourea‐substituted benzenesulfonamides as carbonic anhydrase inhibitors
Mehtap Tugrak, Halise İnci Gül, Yeliz Demir, İlhami Gülçın
Abstract
Abstract The novel compounds with the chemical structure of N ‐({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. The K i values of compounds 1a – g were 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 the K i values of compounds 2a – g were 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 the K i values of the final compounds and acetazolamide, compound 1c with the sulfanilamide moiety ( K i = 5.69 ± 0.43 nM, 8.8 times) and 2f with 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, compounds 1d ( K i = 20.73 ± 4.32, 4 times) and 2d ( K i = 13.98 ± 2.57, 5.9 times), which have the sulfathiazole moiety, were found as potent hCA I inhibitors. Compounds 1c and 2f can be considered as the lead compounds determined in the present study, which can be investigated further to alleviate glaucoma symptoms.