Design, Synthesis, and Pharmacological Evaluation of -Propargylated Diphenylpyrimidines as Multitarget Directed Ligands for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD), a multifactorial complex neural disorder, is categorized with progressive memory loss and cognitive impairment as main clinical features. The multitarget directed ligand (MTDL) strategy is explored for the treatment of multifactorial diseases such as cancer and AD. Herein, we report the synthesis and screening of 24 -propargyl-substituted diphenylpyrimidine derivatives as MTDLs against acetylcholine/butyrylcholine esterases and monoamine oxidase enzymes. In this series, showed the most potent MAO-B inhibitory activity with an IC value of 0.04 ± 0.002 μM. with an IC value of 0.04 ± 0.003 μM and a selectivity index of 626 (over BuChE) displayed the most potent AChE inhibitory activity in this series. In the reactive oxygen species (ROS) inhibition studies, reduced intercellular ROS levels in SH-SY5Y cells by 36%. This series of compounds also exhibited potent neuroprotective potential against 6-hydroxydopamine-induced neuronal damage in SH-SY5Y cells with up to 90% recovery. In the studies in the rats, the hydrochloride salt of was orally administered and found to cross the blood-brain barrier and reach the target site. significantly attenuated the spatial memory impairment and improved the cognitive deficits in the mice. This series of compounds were found to be irreversible inhibitors and showed no cytotoxicity against neuronal cells. In studies, the compounds attained thermodynamically stable orientation with complete occupancy at the active site of the receptors. Thus, -propargyl-substituted diphenylpyrimidines displayed drug-like characteristics and have the potential to be developed as MTDLs for the effective treatment of AD.