Synthesis, molecular docking analysis, drug-likeness evaluation, and inhibition potency of new pyrazole-3,4-dicarboxamides incorporating sulfonamide moiety as carbonic anhydrase inhibitors

Abstract

A series of novel pyrazole-dicarboxamides were synthesized from pyrazole-3,4-dicarboxylic acid chloride and various primary and secondary sulfonamides. The structures of the new compounds were confirmed by FT-IR, ¹H-NMR, ¹³C-NMR, and HRMS. Then the inhibition effects of newly synthesized molecules on human erythrocyte hCA I and hCA II isoenzymes were investigated. K_i values of the compounds were in the range of 0.024-0.496 µM for hCA I and 0.006-5.441 µM for hCA II. Compounds 7a and 7i showed nanomolar level of inhibition of hCA II, and these compounds exhibited high selectivity for this isoenzyme. Molecular docking studies were performed between the most active compounds 7a, 7b, 7i, and the reference inhibitor AAZ and the hCAI and hCAII to investigate the binding mechanisms between the compounds and the isozymes. These compounds showed better interactions than the AAZ. ADMET and drug-likeness analyses for the compounds have shown that the compounds can be used pharmacologically in living organisms.

Keywords: carbonic anhydrase; inhibition; molecular docking; pyrazole‐dicarboxamide; sulfonamide.