6-Substituted nicotinic acid analogues, potent inhibitors of CAIII, used as therapeutic candidates in hyperlipidemia and cancer

Nicotinic acid has been reported as a potential inhibitor of carbonic anhydrase III enzyme. Carbonic anhydrase III (CAIII) is an emerging new pharmacological target for the management of dyslipidemia and cancer progression. The activity of 6-substituted nicotinic acid analogs against carbonic anhydrase III was studied using a size-exclusion chromatography. The appearance of concentration-dependent vacancy peak was indicative of binding with CAIII. Chromatographic and docking studies revealed that the carboxylic acid of ligand is essential for binding via coordinate bond formation with Zn+2 ion in the enzyme active site. Moreover, the presence of a hydrophobic group, containing a hydrogen bond acceptor, at position 6 of the pyridine improves activity, e.g., 6-(hexyloxy) pyridine-3-carboxylic acid (Ki = 41.6 µM). Utilizing the weak esterase activity of CAIII, the inhibitory mode of 6-substituted nicotinic acid was confirmed.