Exploring the potential of pyrazoline containing molecules as Aß aggregation inhibitors in Alzheimer's disease.

ABSTRACT

Objectives Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease in which one of the most prominent pathological features is accumulation of amyloid (Aß) plaques. This occurs due to the process of aggregation from monomeric to polymeric forms of Aß peptide and thus represents one of the attractive targets to treat AD. Methods After initial evaluation of a set of molecules containing N-acetylpyrazoline moiety flanked by aromatic rings on both sides as Aß aggregation inhibitors, the most potent molecules were further investigated for mechanistic insights. These were carried out by employing techniques such as circular dichroism (CD) spectroscopy, transmission electron microscopy (TEM), in vitro PAMPA-BBB (Blood-Brain Barrier) assay and cytotoxicity evaluation. Results Two molecules among the exploratory set displayed Aß aggregation inhibition comparable to standard curcumin. Among the follow-up molecules, several molecules displayed more inhibition than curcumin. These molecules displayed good inhibitory activity even at lower concentrations. CD and TEM confirmed the mechanism of Aß aggregation. These molecules were found to alleviate Aß induced cytotoxicity. BBB penetration studies highlighted the potential of these molecules to reach central nervous system (CNS). Conclusions Thus, several promising Aß-aggregation inhibitors were obtained as a result of this study.