Síntese e avaliação farmacológica de análogos triazólicos e cinamoil-N-acilidrazônicos multialvo contra as doenças de alzheimer e parkinson

Abstract

Neurodegenerative diseases (NDs) are a group of neurological diseases, with Alzheimer’s (AD) and Parkinson’s (PD) diseases as main examples, which show some common pathophysiological aspects such as deposition of insoluble proteins, neuroinflammation, imbalance in the homeostasis of pro- and anti-oxidant processes into the brain. They are progressive, debilitating, with very restrict therapeutical arsenal and, to date, incurable. The goal of this work was the design, synthesis, characterization and pharmacological evaluation of two new series of compounds planned by molecular hybridization of structural fragments of curcumin (1) and resveratrol (2). These two series differ by the nature of the structural subunits derived from curcumin and resveratrol, connected by an N-acyl-hydrazone spacer subunit (series 1). In the series 2, the N-acyl-hydrazone function is linked to a 1,4- disubstituted triazole system as a connection between a 4-hidroxy-3-methoxy-aryl system, inspired in curcumin, and a substituted styrene-type system that mimics one of the aromatic fragments of resveratrol (or curcumin). Among 10 compounds from series 1, one may highlight PQM-161, PQM-163 and PQM-164 that showed good antioxidant activity towards different pro-oxidant agents (ED50 DPPH = 19.98; 29.91 and 0.93 M and IC50 t-BOOH = 0.71; 0.20 and 0.51 M, respectively) and neuroprotective activity against 6-OHDA and - synuclein aggregates induced toxicity, which is a model for evaluation the neuroprotection in PD. Additional studies evidenced that compounds PQM-161 and PQM-164 have a mechanism of intracellular antioxidant activity related to the activation of the nuclear factor erythroid 2-related (Nrf2). Further on-going studies aim to verify the anti-neuroinflammatory activity of PQM-164. Among 13 substances from series 2, PQM-233 showed the best capacity to inhibit acetylcholinesterase (AChE) activity (IC50= 20.6 M), with direct antioxidant activity (EC50 DPPH= 30.44 M and inhibition of t-BOOH at 10 μM of 29.79%) and neuroprotective activity against A oligomers-induced toxicity. All compounds from this work had their toxicity evaluated towards human neuroblastoma cells (SH-SY5Y) and primate renal cell (VERO) in the MTT test and the most active substances highlighted showed no detectable toxicity at the tested concentrations. Finally, we can conclude that the proposed objectives were reaching, PQM-164 and PQM-233 presented multi-target properties against NDs, respectively PD and AD.