Design, synthesis, and biological evaluation of tetrahydropyrimidine analogue as GSK-3β/Aβ aggregation inhibitor and anti-Alzheimer's agent

The complex nature of Alzheimer's disease (AD) etiopathology is among the principal hurdles to developing effective anti-Alzheimer agents. Tau pathology and Amyloid-beta (A beta) accumulation are hallmarks and validated therapeutic strategies of AD. GSK-3 beta is a serine/threonine kinase involved in tau phosphorylation. Its excessive activity also contributes to the production of A beta plaques, making GSK-3 beta an attractive AD target. Taking this into account, In this article, we outline the design, synthesis, and biological validation of a focused library of 1,2,3,4tetrahydropyrimidine based derivatives as inhibitors of GSK-3 beta, tau phosphorylation, and A beta accumulation. The inhibitory activity of forty nine synthetic compounds was tested against GSK-3 beta and other AD-relevant kinases. The kinetic experiments revealed the mode of GSK-3 beta inhibition by the most potent compound 44. The in- vitro drug metabolism and pharmacokinetic studies were thereafter performed. The anti-aggregation activity of the most potent GSK-3 beta inhibitor was tested using AD transgenic Caenorhabditis elegans (C. elegans) strain CL2006 for quantification of A beta plaques and BR5706 C. elegans strain for tau pathology evaluation. We then evaluated the blood-brain barrier permeability and got promising results. Therefore, we present compound 44 as a potential ATP-competitive GSK-3 beta inhibitor with good metabolism and pharmacokinetic profile, anti-aggregation properties for amyloid beta protein, and reduction in tau-phosphorylation levels. We recommend more investigation into compound 44-based small molecules as possible targets for AD disease-modifying treatments.