Exploration of Aromatic Hydrazides as Inhibitors of Human Carbonic Anhydrases

A large set of hydrazide-based derivatives were explored as inhibitors of the human (h) carbonic anhydrase (CA) isoforms I, II, IV, IX, and XII. A wide series of compounds were synthesized and then assessed for their CA inhibitory activity using a CO₂ hydrase stopped-flow assay. Generally, these inhibitors demonstrated micromolar activity against the evaluated hCAs. Specifically, some derivatives bearing a ureido-linker exhibited the highest inhibitory potency, showing inhibition constants (K_Is) in the low-micromolar range against hCAs IV, XI, and XII. Moreover, two of them were detected as submicromolar inhibitors of isoform IV (K_Is: 0.8-0.96 µM). Molecular modeling was carried out to investigate the binding mode of the most selective and potent compounds and reinforce the experimental results. The latter suggests that hydrazide compounds act as zinc binders, being bidentate ligands, and can be developed as an alternative to classic CA inhibitors.