Synthesis and Evaluation of Amide and Thiourea Derivatives as Carbonic Anhydrase (CA) Inhibitors.

Series of sulfonamide-substituted amide ( 9 - 11 ), benzamide ( 12 - 15 ), and 1,3-disubstituted thiourea ( 17 - 26 ) derivatives were synthesized from a common precursor, i.e., substituted benzoyl chlorides. Structures of all of the synthesized compounds were characterized by spectroscopic techniques ( 1 H nuclear magnetic resonance (NMR), 13 C NMR, and Fourier transform infrared spectroscopy (FTIR)). All of the amide ( 9 - 15 ) and thiourea ( 17 - 26 ) derivatives were screened against human carbonic anhydrases, h CA-II, h CA IX, and h CA-XII. Sulfonamide-substituted amides 9 , 11 , and 12 were found to be excellent selective inhibitors with IC 50 values of 0.18 ± 0.05, 0.17 ± 0.05, and 0.58 ± 0.05 μM against h CA II, h CA IX, and h CA XII, respectively. Compound 9 was found to be highly selective for hCA II and about 6-fold more potent as compared to the standard antagonist, acetazolamide. Safe toxicity profiling of the most potent and selective compounds was determined against normal BHK-21 and HEK-293 T cells. Molecular docking studies were performed, which described the type of interactions between the synthesized compounds and enzyme proteins. In addition, in silico absorption, distribution, metabolism, and excretion (ADME) studies were performed, which showed that all of the synthesized molecules fulfilled the druggability criteria.