Natural coumarins from Murraya paniculata as mixed-type inhibitors of cholinesterases: In vitro and in silico investigations

Abstract

Currently, acetylcholinesterase (AChE) inhibiting drugs in clinical use, such as tacrine, donepezil, rivastigmine, and galanthamine, are associated with serious side effects and short half-lives. In recent years, numerous phytochemicals have been identified as inhibitors of cholinesterases with potential applications in the management of Alzheimer’s disease (AD). In this study three natural coumarins, 2′-O-ethylmurrangatin (1), murranganone (2), and paniculatin (3) isolated previously by our group from the leaves of Murraya paniculata, were tested against the two cholinesterases (ChE) enzymes, AChE and butyrylcholinesterase (BChE) using in vitro assay. Molecular docking was performed to highlight the structural properties that contribute to the molecular recognition pattern in the inhibition of ChE and the structural differences resulting in the selectivity of these compounds toward AChE. Classical enzyme inhibition kinetics data suggested that compounds 2 and 3 were potent inhibitors of AChE and BChE, while 1 was found inactive against both enzymes. The findings from molecular docking studies revealed the competitive and non-competitive inhibition mechanisms of compounds 2 and 3 against both enzymes. Molecular docking and simulations have revealed that hydrogen bonding, mediated by ketone and hydroxyl functionalities in various positions, significantly contributes to the binding of the inhibitor to the receptor. According to MD simulation studies, the stability of the ligand-AChE complex for the most active compound (3) is found to be comparable to that of the widely used drug Tacrine. In addition, to evaluate the drug-likeness of compounds, in silico ADME evaluation was performed, and the compounds presented good ADME profiles. Data suggested that the coumarin nucleus having diverse side chains at the C-8 position can serve as a potential inhibitor of cholinesterases and can act as a lead to develop a new semisynthetic drug for the treatment of AD.

A comprehensive review of the botany, phytochemistry, pharmacology, and toxicology of Murrayae Folium et Cacumen

“…Therefore, they can be considered potential candidates for AD treatment. These coumarins show non-selective, moderate-to-good in vitro activity against both AChE and BChE via a mixed-type inhibitory mechanism ( Khalid et al, 2023 ).…”

Coumarin Derivatives: Mechanistic Insights and Promising Applications as Potential Alzheimer's Disease (AD) Therapeutic Agents

“…Structure of coumarin 2'O-ethyl murrangtin and paniculatin (135-136). [44] various position is facilitated by ketone and hydroxyl functionalities of amino acid at various locations considerably aids in the binding of the inhibitor to the receptors. Moreover, the stability of most active molecule is comparable to that of standard drug tacrine.…”

“…Khalid et al [44] reported that naturally derived coumarine 2’O‐ethyl murrangtin and and paniculatin (Figure 26) from the leaves of Murraya paniculata and evaluated in vitro assays against AChE and BChE. Enzyme inhibition results revealed that compound 135 and 136 was shown to be efficient inhibitors of AChE and BChE.…”

Novel 2-substituted-quinoxaline analogs with potential antiproliferative activity against breast cancer: insights into cell cycle arrest, topoisomerase II, and EGFR activity

“…48,49 Systematic research found 1300 secondary metabolite chemotypes in plants, microbes, and fungi. 50 The roots of Ferulago campestris, 51 Murraya paniculata 52 leaves, Aegle marmelos 53 fruits, and tonka bean seeds contain derivatives of coumarins with several biological functions. Synthetic coumarin-based heterocyclic analogues such azoles, sulfonyl, furan, and pyrazole have promise anticancer, antitumor, and anti-proliferative properties.…”