N-aryl-N′-ureido-O-sulfamates as potent and selective inhibitors of hCA VB over hCA VA: Deciphering the binding mode of new potential agents in mitochondrial dysfunctions.

• N -aryl- N ′-ureido- O -sulfamates (AUSs) were investigated as hCA VA and VB inhibitors. • High selectivity against hCA VB over VA was observed for all the compounds. • AUSs resulted to contain privileged chemical fragments for hCA VB selective inhibition. • Molecular modeling showed the different binding modes within the two isoforms. N -aryl- N ′-ureido- O -sulfamates (AUSs) were recently reported as new class of Carbonic Anhydrase Inhibitors (CAIs), endowed of high potency and selectivity against hCA VII and XII. In this work, we extended the investigational study on this new class of CAIs profiling them against the mitochondrial CA isoforms hCA VA and VB. The results revealed a very interesting selectivity profile, with dramatic selectivity against hCA VB over the VA isoform observed for all the analyzed compounds 2 – 22. On derivative 15 , selected as one of the most promising among the series, molecular modeling studies were conducted, highlighting the importance of small residue substitution between the two isoforms in substantially changing the tail orientation and interaction with the enzymes. [ABSTRACT FROM AUTHOR]