Superacid-Synthesized\nFluorinated Diamines Act as\nSelective hCA IV Inhibitors

Carbonic anhydrase (CA) IV is a membrane-bound enzyme\ninvolved\nin important physio-pathological processes, such as excitation-contraction\ncoupling in heart muscle, central nervous system (CNS) extracellular\nbuffering, and mediation of inflammatory response after stroke. Known\nsince the mid-1980s, this isoform is still largely unexplored when\ncompared to other isoforms, mostly for the current lack of inhibitors\ntargeting selectively this isoform. The discovery of selective CA\nIV inhibitors is thus largely awaited. In this work, we report β-(di)\nfluoropropyl diamines as effective CA IV inhibitors, opening real\nperspectives for a new mode of selective inhibition of this isoform.\nInhibition data reveal that the essential structure core to ensure\na potent and selective inhibition of CA IV is the <i>N</i>-propyldiamine. Molecular modeling studies were employed to understand\nthe binding mode of the synthesized amines. Conformational searches\nwithin the active site space carried out in an implicit solvent (water)\nmodel were also conducted.