Carbonic anhydrase activation profile of indole-based derivatives |
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| Authors: | Elisabetta Barresi Rahul Ravichandran Lorenzo Germelli Andrea Angeli Emma Baglini Silvia Salerno Anna Maria Marini Barbara Costa Eleonora Da Pozzo Claudia Martini Federico Da Settimo Claudiu Supuran Sandro Cosconati Sabrina Taliani |
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| Institution: | aDepartment of Pharmacy, University of Pisa, Pisa, Italy;bDiSTABiF, University of Campania Luigi Vanvitelli, Caserta, Italy;cDepartment of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Firenze, Sesto Fiorentino, Italy |
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| Abstract: | Carbonic Anhydrase Activators (CAAs) could represent a novel approach for the treatment of Alzheimer’s disease, ageing, and other conditions that require remedial achievement of spatial learning and memory therapy. Within a research project aimed at developing novel CAAs selective for certain isoforms, three series of indole-based derivatives were investigated. Enzyme activation assay on human CA I, II, VA, and VII isoforms revealed several effective micromolar activators, with promising selectivity profiles towards the brain-associated cytosolic isoform hCA VII. Molecular modelling studies suggested a theoretical model of the complex between hCA VII and the new activators and provide a possible explanation for their modulating as well as selectivity properties. Preliminary biological evaluations demonstrated that one of the most potent CAA 7 is not cytotoxic and is able to increase the release of the brain-derived neurotrophic factor (BDNF) from human microglial cells, highlighting its possible application in the treatment of CNS-related disorders. |
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| Keywords: | Carbonic anhydrase activators indole microglia brain associated human CA VII isoform |
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