Coumarin-pyrazoline Hybrids as Selective Inhibitors of the Tumor-associated Carbonic Anhydrase IX and XII.

AIM: Human carbonic anhydrase (CA, EC 4.2.1.1) isoforms IX and XII are validated antitumor/ antimetastatic drug and tumor imaging targets with sulfonamide inhibitors and monoclonal antibodies in clinical development. Coumarins act as isoform-selective inhibitors of these isoforms over the cytosolic and mitochondrial ones.

METHODS

We report the synthesis and in vitro CA inhibitory evaluation of a large panel of coumarins incorporating pyrazole-1-carboxamide moieties. Compounds were fully characterized before the assessment of their inhibitory activity. A stopped-flow CO2 hydrase assay was performed for the biological test.

RESULTS

These coumarins did not inhibit the widespread, off-target isoforms CA I and II (KI >50 μM), but they were sub-micromolar CA IX/XII inhibitors with an interesting selectivity index higher than the reference compound. Selectivity between α- and β-class of CAs was also promising.

CONCLUSION

These compounds may be used as leads for the rational design and development of non-sulfonamide CA IX/XII effective inhibitors.