Sulfonamides containing coumarin moieties selectively and potently inhibit carbonic anhydrases II and IX: Design, synthesis, inhibitory activity and 3D-QSAR analysis

•18 Novel sulfonamides containing coumarin moieties had been synthesized.•Most of the compounds showed low toxicity to human macrophage cells.•Compound 5l showed the most potent and best selective hCA IX inhibition.•We built a 3D-QASR model for the further explanation of SAR about these compounds.

A series of sulfonamides containing coumarin moieties had been prepared that showed a very interesting profile for the inhibition of two human carbonic anhydrase inhibitors. These compounds were evaluated for their ability to inhibit the enzymatic activity of the physiologically dominant isozymes hCA II and the tumor-associated isozyme hCA IX. The most potent inhibitor against hCA II and IX were compounds 5d (IC50 = 23 nM) and 5l (IC50 = 24 nM), respectively. These sulfonamides containing coumarin moieties may prove interesting lead candidates to target tumor-associated CA isozymes, wherein the CA domain is located extracellularly. Eighteen compounds were scrutinized by CoMFA and CoMSIA techniques of 3D quantitative structure–activity relationship. Nine of the compounds were evaluated for cytotoxicity against human macrophage.

Graphical abstractA series of sulfonamides containing coumarin moieties had been designed, synthesized, isolated and evaluated as inhibitors of two human carbonic anhydrase. Compounds 5d exhibited the most potent hCA II inhibitory activity.Figure optionsDownload full-size imageDownload as PowerPoint slide