RESUMO
In excitable cells, mitochondria play a key role in the regulation of the cytosolic Ca2+ levels. A dysregulation of the mitochondrial Ca2+ buffering machinery derives in serious pathologies, where neurodegenerative diseases highlight. Since the mitochondrial Na+/Ca2+ exchanger (NCLX) is the principal efflux pathway of Ca2+ to the cytosol, drugs capable of blocking NCLX have been proposed to act as neuroprotectants in neuronal damage scenarios exacerbated by Ca2+ overload. In our search of optimized NCLX blockers with augmented drug-likeness, we herein describe the synthesis and pharmacological characterization of new benzothiazepines analogues to the first-in-class NCLX blocker CGP37157 and its further derivative ITH12575, synthesized by our research group. As a result, we found two new compounds with an increased neuroprotective activity, neuronal Ca2+ regulatory activity and improved drug-likeness and pharmacokinetic properties, such as clog p or brain permeability, measured by PAMPA experiments.
Assuntos
Doenças Neurodegenerativas/tratamento farmacológico , Neurônios/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores , Acidente Vascular Cerebral/tratamento farmacológico , Tiazepinas , Animais , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Mitocôndrias , Neurônios/patologia , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Ratos , Tiazepinas/síntese química , Tiazepinas/farmacologiaRESUMO
As part of our ongoing studies on the synthesis of bioactive coumarin compounds, we synthesized a series of new coumarin-fused 1,4-thiazepines using a simple method. The biological activity of target compounds along with 3-(2-hydroxybenzylidene)chroman-2,4-dione intermediates was screened by evaluation of their antioxidant and cytotoxic activities. The antioxidant activity was assessed using two methods, namely, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging method and ferric reducing antioxidant power (FRAP) assay. 4-Methoxyphenolic compound 5d in thiazepine series showed the most potent scavenging activity, while the 4-bromophenolic derivative 5b was the most efficient compound in FRAP assay. Also, the result of cytotoxic evaluation using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay demonstrated that compound 5b is at least twofold more potent than etoposide against MCF-7, SK-N-MC, and MDA-MB 231 cell lines.