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.

Carbonic anhydrase activation profile of indole-based derivatives

Elisabetta Barresi
Primo
;
Lorenzo Germelli;Emma Baglini;Silvia Salerno;Anna Maria Marini;Barbara Costa;Eleonora Da Pozzo;Claudia Martini;Federico Da Settimo;Sabrina Taliani
Ultimo
2021-01-01

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.
2021
Barresi, Elisabetta; Ravichandran, Rahul; Germelli, Lorenzo; Angeli, Andrea; Baglini, Emma; Salerno, Silvia; Marini, ANNA MARIA; Costa, Barbara; DA POZZO, Eleonora; Martini, Claudia; DA SETTIMO PASSETTI, Federico; Supuran, Claudiu; Cosconati, Sandro; Taliani, Sabrina
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/1105092
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