Design, Synthesis and Evaluation of O‐Pentyne Substituted Diphenylpyrimidines as Monoamine Oxidase and Acetylcholinesterase Inhibitors

• Published in: ChemistrySelect (Weinheim) 2020-07, Vol.5 (27), p.8021-8032
• Main Authors: Kumar, Vijay, Kumar, Bhupinder, Ranjan Dwivedi, Ashish, Mehta, Devashish, Kumar, Naveen, Bajaj, Beenu, Arora, Tania, Prashar, Vikash, Parkash, Jyoti, Kumar, Vinod
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase inhibitors; Alzheimer's disease; Biological activity; Drug design; MAO inhibitor; Neurological disorders; Pyrimidine derivatives; Reversible inhibitors
• ISSN: 2365-6549; 2365-6549
• DOI: 10.1002/slct.202002425

Alzheimer's disease (AD) is a multifactorial neurological disorder and single target directed drugs have been found ineffective in the retardation or reversal of disease state. In last few years, multi‐targeting agents are being explored as drug strategy for the effective treatment of AD. A series of (4‐(pent‐4‐yn‐1‐yloxy)phenyl)‐2‐phenylpyrimidine derivatives has been synthesized and evaluated against monoamine oxidase (MAO) and acetylcholinesterase (AChE) enzymes. Most of the synthesized compounds were found to be potent inhibitors of MAO−A, MAO−B and AChE enzymes with IC50 values in low micromolar range. In the series, BD‐13 and BD‐14 were found to be the most potent dual inhibitors of MAO−A and AChE enzymes. BD‐13 showed MAO−A and AChE inhibition with IC50 values of 0.78±0.12 μM and 2.84±0.19 μM, respectively. Similarly, BD‐14 showed potent inhibition activities against MAO−A and AChE enzymes with IC50 values of 0.75±0.04 μM and 2.19±0.06 μM, respectively. In reversibility studies, BD‐13 and BD‐14 were found to be reversible inhibitors of both MAO−A and AChE enzymes. In the cytotoxicity studies, BD‐13 and BD‐14 were found to be non‐toxic to the SH‐SY5Y cells. In the molecular dynamic simulation studies of 30 ns, both the potent compounds were found to be thermodynamically stable in the active sites of MAO−A and AChE. Thus, BD‐13 and BD‐14 can be used as lead compounds for the development of more potent compounds for the effective treatment of Alzheimer's disease. A total of 14 (4‐(pent‐4‐yn‐1‐yloxy)phenyl)‐2‐phenylpyrimidine derivatives have been synthesized and screened for monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitory activities. Compounds BD‐13 and BD‐14 were found to be the most potent dual inhibitors of MAO−A and AChE enzymes. In addition, BD‐13 and BD‐14 were found to be reversible inhibitors of both MAO−A and AChE enzymes and non‐toxic to the SH‐SY5Y cells.