Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 177, Issue -, Pages 221-234Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.05.039
Keywords
Alzheimer's disease; MAO inhibitors; Acetylchollnesterase inhibitors; Diphenylpyrimidine; Dual inhibitors; Neurological disorders
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Funding
- DST-SERB [EMR/2015/002339, ECR/2015/000240]
- Central University of Punjab, Bathinda [RSM GP25]
- CUP, Bathinda
- CSIR
- UGC
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Alzheimer's disease (AD) is a multifactorial neurological disorder involving complex pathogenesis. Single target directed drugs proved ineffective and since last few years' different pharmacological strategies including multi-targeting agents are being explored for the effective drug development for AD. A total of 19 dipropargyl substituted diphenylpyrimidines have been synthesized and evaluated for the monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibition potential. All the compounds were found to be selective and reversible inhibitors of MAO-B isoform. These compounds also displayed good AChE inhibition potential with IC50 values in low micromolar range. AVB4 was found to be the most potent MAO-B inhibitor with IC50 value of 1.49 +/- 0.09 mu M and AVB1 was found to be the most potent AChE inhibitor with IC50 value of 135 +/- 0.03 mu M. In the ROS protection inhibition studies, AVB1 and AVB4 displayed weak but interesting activity in SH-SYSY cells. In the cytotoxicity studies involving SH-SY5Y cells, both AVB1 and AVB4 were found to be non-toxic to the tissue cells. In the molecular dynamic simulation studies of 30 ns, the potent compounds were found to be quite stable in the active site of MAO-B and AChE. The results suggested that AVB1 and AVB4 are promising dual inhibitors and have the potential to be developed as anti-Alzheimer's drug. (C) 2019 Published by Elsevier Masson SAS.
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