3-(1H-pyrazole-1-yl/1H-1,2,4-triazole-1-yl)-N-propananilide derivatives: Design, synthesis and neuroprotectivity potential against 6-OHDA induced neurotoxicity model

INTRODUCTION: Excessive amounts of neuroapoptosis are the underlying cause of neurodegenerative diseases. Bax is a pro-apoptotic member of the Bcl-2 family that activates caspases which are the members of cysteine protease family that plays significant role in the initiation and execution phases of apoptosis.
In this study, a group of N-propananilide derivatives bearing pyrazole or 1,2,4-triazole ring were designed and synthesized to analyse the neuroprotectivity potential against 6‐OHDA and four compounds possessed protectivity at lower doses were subjected to further studies on caspase-3 and Bax pathway.

METHODS: Designed compounds were synthesized by reacting 1H-pyrazole or 1H-1,2,4-triazole with propananilide intermediates in DMF. Neuroprotective activity of the title compounds was analysed against 6-OHDA induced neurotoxicity model. Then, caspase-3 and Bax levels were determined for the selected compounds by Western Blot study.
RESULTS: All twelve 3-(1H-pyrazole-1-yl/1H-1,2,4-triazole-1-yl)-N-propananilide derivatives possessed neuroprotectivity against 6-OHDA induced neurotoxicity model. Compounds 7, 10, 11, and 12 were found to be more active at lower doses also, therefore, they were subjected to further studies and the results revealed that their protecting activity arise from the decreasing the levels of Bax, one of the pro-apoptotic proteins, and c expression levels and caspase-3 proteins.
DISCUSSION AND CONCLUSION: All designed and synthesized derivatives possessed neuroprotectivity against 6-OHDA induced neurotoxicity in SH-SY5Y cell line and compounds 7, 10, 11, and 12 revealed that their neuroprotectivity is originated from the decreasing the bax expression levels and caspase-3 activation.