The family of carbonic anhydrases (CAs, EC 126.96.36.199) includes several metalloenzymes highly abundant in prokaryotes and eukaryotes. There are 16 human CA (hCA) isoforms having different tissue and cellular localizations. Their catalytic domain is formed by zinc(II) ion reacting with carbon dioxide to give bicarbonate that is an essential physiological reaction, which controls many physiological processes. Among the different hCA isoforms, hCA VII, hCA IX, and hCA XIV have recently been shown to be druggable targets. In particular, the hCA VII is expressed in the mammalian brain, where is involved in generating neuronal excitation and seizures. On this basis, we focused our research on the development of CA inhibitors (CAIs) showing high potency and selectivity against the hCA VII isoform thus avoiding unwanted off target effects.1-3 Thus we planned the synthesis of a small series of 1,2,3,4-tetrahydroisoquinoline which showed a high capacity to efficiently inhibit hCA VII isozyme (Ki values between 2.8 nM and 4 nM). In order to obtain an improved selectivity towards the hCA VII isoform, we modified the chemical structure and added a bulky aromatic portion. Using computational approaches, we also explored the inhibitory mechanism of action of the designed compounds. We herein report the main research findings about this new class of CAIs considering both structure-activity relationships (SAR) and enzyme/inhibitor interactions within the catalytic pocket.
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