Journal
ACS CHEMICAL NEUROSCIENCE
Volume 13, Issue 14, Pages 2122-2139Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.2c00132
Keywords
Alzheimer's disease; MAO inhibitors; diphenylpyrimidine; acetylcholinesterase inhibitors; multitarget directed ligands; neuroprotective agents
Funding
- Council of Scientific and Industrial Research, New Delhi [02/ (0354) /19/EMRII]
- SERB DST [ECR/2015/000240, CRG/2020/003257]
- ISF College of Pharmacy, Moga, Punjab
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This study reports a series of N-propargyl-substituted diphenylpyrimidine derivatives with potential inhibitory activity against AChE and MAO-B, as well as neuroprotective effects and improvement of cognitive function.
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 N-propargyl-substituted diphenylpyrimidine derivatives as MTDLs against acetylcholine/ butyrylcholine esterases and monoamine oxidase enzymes. In this series, VP1 showed the most potent MAO-B inhibitory activity with an IC50 value of 0.04 & PLUSMN; 0.002 mu M. VP15 with an IC50 value of 0.04 & PLUSMN; 0.003 mu M 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, VP1 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 in vivo studies in the rats, the hydrochloride salt of VP15 was orally administered and found to cross the blood-brain barrier and reach the target site. VP15 & BULL; HCl 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 in silico studies, the compounds attained thermodynamically stable orientation with complete occupancy at the active site of the receptors. Thus, N- propargyl-substituted diphenylpyrimidines displayed drug-like characteristics and have the potential to be developed as MTDLs for the effective treatment of AD.
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