Synthesis and Carbonic Anhydrase Inhibition Profiles of N-(3-sulfamoylphenyl)propanamide/benzamide Derivatives: Experimental and Computational Insights With Absorption, Distribution, Metabolism, and Excretion Profiling

Carbonic anhydrases (CA) I and II are the most abundant CA isozymes in erythrocytes and have been therapeutic targets in treating glaucoma, hypertension, ulcers, osteoporosis, and, neurological disorders. In this study, N-(3-sulfamoylphenyl) propanamide/benzamide derivatives were synthesized. Then, the CA isozymes were isolated and the inhibitory effects of the synthesized derivatives on these Enzymes were investigated experimentally. The mechanism of inhibition was estimated by molecular docking studies. Finally, the Absorption, Distribution, Metabolism, and Excretion properties of derivatives were evaluated and analyzed in terms of pharmacokinetics and drug similarity. P4 was the most effective inhibitor among derivatives against both hCA-I and hCA-II with K_i constants as 0.22 ± 0.01 and 0.33 ± 0.05 µM, respectively. Besides, P4 had a higher binding affinity to both Enzymes with free binding energies of -8.14 and -8.03 kcal/mol. According to drug-likeness analysis, it was predicted that the derivatives comply with Lipinski's rule of five without any deviation.

benzenesulfonamides; carbonic anhydrases; inhibition; molecular docking; structure‐activity relationship.