Design, synthesis, and biological evaluation of Propargylated phenyl‐styryl‐pyrimidine derivatives as dual inhibitors of monoamine oxidase and acetylcholinesterase
Kailash Jangid, Bharti Devi, Vijay Kumar, Vinod Kumar- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Alzheimer’s disease (AD) is a neurological disorder, and its etiology is not completely known. Due to its multifactorial nature different theories were proposed for its initiation and progression including amyloid cascade hypothesis; tau hypothesis; cholinergic hypothesis, excitotoxicity hypothesis, mitochondrial cascade hypothesis. Various attempts are made, aimed to intervene with different target sites including amyloid‐β peptide (Aβ), acetylcholinesterase (AChE), tau protein, monoamine oxidase (MAO), β ‐site amyloid‐Precursor protein‐cleaving Enzyme 1 (BACE‐1), free radicals and metal ions (Fe2+, Cu2+, Zn2+), in order to control the AD. Previously approved drugs are based on the one drug one biological target strategy but over the past several years multi‐target directed ligands (MTDL) strategy has gained much interest in the development of effective inhibitors for the treatment of AD.
Method
Based on our previous research work on MTDLs, in the current work we report the synthesis of phenyl‐styryl‐pyrimidine derivatives designed by taking pharmacophore from previously reported molecules and evaluated the effect of extended conjugation in pyrimidine functionalization against MAO‐B and AChE inhibition. In vitro Screening of the synthesized compounds as inhibitors of the cholinesterases and MAO enzymes using Ellman’s and Amplex red assay. This study is also supported by computational tools like‐ molecular docking, molecular dynamics, pharmacokinetics properties etc.
Result
Compound VKB‐3 was found to be the most potent MAO‐B inhibitor with an IC50 value of 4.93 μM. Additionally, it exhibits strong inhibition of AChE, with an IC50 value of 9.016 µM. Similarly, compound VKB‐14, displayed inhibition for MAO‐B with an IC50 of 7.265 µM and for AChE with an IC50 of 9.291 µM. In the Lineweaver‐Burk reciprocal plots, both VKB ‐3 and VKB ‐14 exhibited hyperbolic non‐competitive type inhibition. In the docking studies, VKB‐3 and VKB‐14 displayed good affinity towards AChE (‐7.095 and ‐6.767 kcal/mol) and MAO‐B (‐8.548 and ‐11.20 kcal/mol), respectively. MD simulation study suggested that the compound VKB‐14 was able to form more stable complex with both the targeted proteins.
Conclusion
VKB‐14 was found as potential lead, which showed good inhibition against both AChE and MAO‐B enzymes. It can be further optimized as MTDL for the treatment of AD.