Inhibition of α-class cytosolic human carbonic anhydrases I, II, IX and XII, and β-class fungal enzymes by carboxylic acids and their derivatives: New isoform-I selective nanomolar inhibitors

Abstract

The members of a focused series of carboxylic acids and of their derivatives (esters, amides and metal complexes) have been investigated as inhibitors of the main cytosolic/transmembrane carbonic anhydrase isoforms, CA I, II, IX and XII, belonging to the mammalian α-class of CAs. These enzymes are present in red blood cells in submillimolar concentration, and typical sulfonamide CA inhibitors do not selectively inhibit any of them. Among such isozymes, the isoform-I is an ‘orphan’ target that mediates hemorrhagic retinal and cerebral vascular permeability, involved in retinal and cerebral disease. In the present study, we identified the first selective CA I nanomolar inhibitors, that displayed activity against other isozymes in micromolar/millimolar concentration range. Selective CA II over CA I inhibition has also been observed with some diketo acids/metal complexes. Few diketo acid derivatives showed inhibition activities against the fungal β-class enzymes from Candida albicans and Cryptococcus neoformans in low micromolar concentration range. Prediction of drug-like properties for the most interesting compounds suggests a favorable bioavailability.