N -Nitrosulfonamides as Carbonic Anhydrase Inhibitors: A Promising Chemotype for Targeting Chagas Disease and Leishmaniasis.

Autor: Bonardi A; Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino (Firenze), Italy.; Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Firenze, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy., Vermelho AB; BIOINOVAR-Biotechnology Laboratories: Biocatalysis, Bioproducts and Bioenergy, Institute of Microbiology Paulo de Góes, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil., da Silva Cardoso V; Laboratory of Cellular Ultrastructure, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, 21040-900 Rio de Janeiro, RJ, Brazil., de Souza Pereira MC; Laboratory of Cellular Ultrastructure, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, 21040-900 Rio de Janeiro, RJ, Brazil., da Silva Lara L; Laboratory of Cellular Ultrastructure, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, 21040-900 Rio de Janeiro, RJ, Brazil., Selleri S; Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Firenze, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy., Gratteri P; Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Firenze, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy., Supuran CT; Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino (Firenze), Italy., Nocentini A; Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino (Firenze), Italy.; Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Firenze, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2018 Nov 27; Vol. 10 (4), pp. 413-418. Date of Electronic Publication: 2018 Nov 27 (Print Publication: 2019).
DOI: 10.1021/acsmedchemlett.8b00430
Abstrakt: Trypanosoma cruzi and Leishmania spp. are protozoa of the Trypanosomatidae family, respectively, responsible of the neglected tropical disorders (NTDs) Chagas disease and leishmaniasis. The present pharmacotherapy is often ineffective and exhibits serious side effects. The metalloenzyme carbonic anhydrases (CAs, EC 4.2.1.1) recently identified in these protozoans (α-TcCA and β-LdcCA) are novel promising targets for chemotherapeutic interventions. Herein, we report a series of N -nitrosulfonamides, as a novel chemotype to yield the target CA isoform selective inhibition over ubiquitous human isozymes. Two derivatives selected among the most active and selective ones for TcCA/LdcCA over off-target CAs were progressed as silver salts to in vitro studies with various developmental forms and spp of Trypanosoma cruzi and leishmania. Excellent values of parasites growth inhibition (IC 50 ) were observed, with some selectivity index (over cytotoxicity for macrophages and Vero cells) being comparable or better than reference drugs. These findings make N -nitrosulfonamides and their salts promising lead compounds for a rational optimization of innovative agents for the treatment of Chagas disease and leishmaniasis based on CA inhibition.
Competing Interests: The authors declare no competing financial interest.
Databáze: MEDLINE
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