Synthesis and Biological Assessment of 4,1-Benzothiazepines with Neuroprotective Activity on the Ca2+ Overload for the Treatment of Neurodegenerative Diseases and Stroke

Abstract

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.

Polyfunctionalized α-Phenyl-tert-butyl(benzyl)nitrones: Multifunctional Antioxidants for Stroke Treatment

“…The MTT reduction method was selected to evaluate the neuroprotective profile of selected compounds in an in vitro neurodegeneration model [ 29 ]. Briefly, the SH-SY5Y neuroblastoma cell culture was maintained and seeded, as previously described [ 30 ]. After 24 h of cell culturing, the cells were treated with 1 , 5 , or 6 at the concentrations indicated in Figure 5 for an additional 24 h. Then, the medium was replaced with a fresh one containing FBS 1%, compounds, and OA at a final concentration of 20 nM.…”

The initiator of neuroexcitotoxicity and ferroptosis in ischemic stroke: Glutamate accumulation

“…Results of a meta-analysis show no effect of calcium antagonists on primary patient outcomes or death, and researchers show no evidence to support the use of calcium antagonists in patients with ischaemic stroke as beneficial ( Zhang et al, 2019 ). 4,1-benzothiazoles are non-calcium antagonist drugs that reduce calcium levels in neurons by modulating mitochondria ( Viejo et al, 2021 ). Calcium antagonists continue to be the subject of stroke research, although they have not achieved the desired results in clinical trials, probably because of intolerable side effects, low efficacy and short treatment windows.…”

Promising Molecular Targets in Pharmacological Therapy for Neuronal Damage in Brain Injury

“…The selected strategy was the ring variation, namely turning the benzene-fused ring present in CGP37157, ITH12505 or ITH12575, into pyridine, to furnish pyridothiazepine derivatives (Figure 3) [113]. As an alternative, the replacement of the chlorine atom at C7 of the benzothiazepine ring with a dimethylamino group also afforded CGP37157 with low clog P [114]. The replacement of the benzene by a pyridine-fused ring enhanced the global polarity of molecules, as demonstrated by comparing clog P among similar analogs of this series.…”

“…Experimentally, the aqueous solubility augmented noticeably, observed by UV-vis absorption spectra, as benzothiazepine derivatives col-Figure 3. Chemical structures of CGP37157 (first left) and selected third generation analogues with improved pharmacokinetic properties [113,114].…”

“…Figure 3. Chemical structures of CGP37157 (first left) and selected third generation analogues with improved pharmacokinetic properties[113,114].…”