3-(1H-pyrazole-1-yl/1H-1,2,4-triazole-1-yl)-N-propananilide Derivatives: Design, Synthesis and Neuroprotectivity...

Excessive amounts of neuroapoptosis are the underlying cause of neurodegenerative diseases. Bax is a pro-apoptotic member of the B-cell lymphoma-2 family that activates caspases which are the members of the cysteine protease family that play a significant role in the initiation and execution phases of apoptosis. The aim of this study was to design and synthesize a group of N-propananilide derivatives bearing pyrazole or 1,2,4-triazole ring were designed and synthesized to analyze the neuroprotectivity potential against 6-hydroxy-dopamine (6-OHDA). Four compounds possessed protectivity at lower doses were subjected to further studies on caspase-3 and Bax pathway.

Designed compounds were synthesized by reacting 1H-pyrazole or 1H-1,2,4-triazole with propananilide intermediates in Dimethylformamide. The neuroprotective activity of the title compounds was analyzed against 6-OHDA-6-OHDA-induced neurotoxicity model. Then, caspase-3 and Bax levels were determined for the selected compounds by Western blot study.

All twelve 3-(1H-pyrazole-1-yl/1H-1,2,4-triazole-1-yl)-N-propananilide derivatives possessed neuroprotectivity against the 6-OHDA-induced neurotoxicity model (p≤0.05, **p≤0.001, ***p≤0.005). Compounds 7, 10, 11, and 12 were found to be more active at lower doses. They were subjected to further studies and the results revealed that their protecting activity arose from the decreasing levels of Bax, one of the pro-apoptotic proteins, and c expression levels and caspase-3 proteins.

All designed and synthesized derivatives possessed neuroprotectivity against 6-OHDA-induced neurotoxicity in the SH-SY5Y cell line and compounds 7, 10, 11, and 12 revealed that their neuroprotectivity originated from the decreasing Bax expression levels and caspase-3 activation.