Synthesis and biological evaluation of novel hydrogen sulfide releasing nicotinic acid derivatives

Twelve novel hybrids of slowly releasing hydrogen sulfide donor ADT-OH combined with nicotinic acid were synthesized. All of their structures had been confirmed by H-1 NMR, C-13 NMR and MS spectra. The target compounds were evaluated for their neuroprotective effects on hippocampal neuron HT22 cells against glutamate-induced injury at the concentrations of 1-100 mu M with MTT assay, and their toxicity on HT22 cells untreated by glutamine at the concentration of 100 mu M. The active compound was further investigated for its effect on ischemic infarct volume by intraperitoneal injection at 3 h after ischemia in mice models of permanent middle cerebral artery occlusion (pMCAO). The results showed that all the compounds significantly protected HT22 cells from glutamate-induced damage at most of the experimental concentrations, and had no or little neurotoxicity on normal HT22 cells at the high concentration. More importantly, compound A6 significantly reduced infarct volume in the pMCAO model. These results suggested that compound A6 may be promising for further evaluation for the intervention of cerebral ischemic injury. (C) 2016 Published by Elsevier Ltd.