Synthesis and biological evaluation of N/O-propargylated diarylpyrimidines as dual inhibitors of acetylcholinesterase and monoamine oxidase

Abstract

Alzheimer's disease is a complex neurological disorder and is becoming a global health concern as the population ages. Considering the complex aetiology of the disease and ineptness of single-targeted drugs, the development of multi-targeted drugs emerges as the most effective strategy for the treatment of the disease. Cholinesterases and monoamine oxidases are amongst the most widely explored targets in Alzheimer’s disease, and their dual inhibition offers a promising approach for achieving multipotent therapeutic effects. Herein, we designed and synthesized a series of N/O-propargylated diaryl pyrimidines and evaluated their inhibitory activity against acetylcholinesterase (AChE) and monoamine oxidase (MAO) enzymes. Most of the compounds were found to be active against AChE, MAO-A and MAO-B. Amongst the synthesised derivatives of the series, compounds, compounds NV-1 and NV-9 exhibited a balanced multipotent activity profile against both the targets i.e. acetylcholinesterase and monoamine oxidase. Compounds NV-1 and NV-9 displayed IC₅₀ values of 1.30 µM and 0.88 µM against AChE, 0.232 µM and 9.31 µM against MAO-A and 0.949 µM and 9.23 µM against MAO-B, respectively. In the reversibility inhibition studies, both the compounds were found to be reversible in nature. In kinetic inhibition studies, both NV-1 and NV-9 showed non-competitive inhibition for AChE. Additionally, NV-1 and NV-9 were found to be moderately neuroprotective in nature and exhibit no cytotoxicity at lower compound concentrations. In the partition coefficient studies (octanol/water), the compound NV-9 was found to be lipophilic in nature. Molecular docking studies illustrate their stability within the active cavity of both enzymes. Simulation studies confirmed the thermodynamic stability of these compounds within the cavity for up to 100 ns. Thus, the N/O-propargylated diarylpyrimidines have the potential to be developed as multipotent drugs for the treatment of Alzheimer's disease.