Investigation on anti-prion, neuroprotective and anti-cholinesterase activities of acridine derivatives

Abstract

This thesis aims to investigate the hypothesis that acridine is a good template for neurodegenerative diseases. Three conditions were evaluated, namely (i) anti-prion activity (ii) neuroprotective activity in glutamate-induced oxytosis (iii) anti-cholinesterase activities. Structure modifications of the lead compound, quinacrine, involved variation of different types of side chain as well as replacing the acridine to its related variants such as tetrahydroacridine and quinoline. A library of acridine derivatives were designed and synthesized. Evaluation of anti-prion activities on different prion strains identified 4-(methylpiperazyl)phenyl and 1-benzyl-4-piperidinyl side chains as potent and borad-spectrum anti-prion analogs. This led to the synthesis of better and less toxic analogs of these two lead compounds. These compounds bind to but not affect the cellular prion protein levels. Neuroprotective activity required a ?NH- group flanked by a phenyl ring and an aromatic template. This structure allowed compounds to act as antioxidant to reduce the mitochondrial reactive oxygen species level and prevent the influx of calcium, thus rescuing neuronal cells from oxidative stress-induced cell death. A combination between the tetrahydroacridine ring and 1-benzyl-4-piperidinyl side chain resulted in a potent and selective acetylcholinesterase inhibitor. The structure-activity relationships were established for each biological activity in this study. These findings provide the lead for the future development of acridine derivatives as neurodegenerative agents which possess good blood brain barrier permeability.