Piperazine-substituted chalcones: a new class of MAO-B, AChE, and BACE-1 inhibitors for the treatment of neurological disorders.

Bijo Mathew,Hoon Kim,Roua S Baty,Nicola Gambacorta,Gaber El-Saber Batiha,Della Grace Thomas Parambi,Jong Min Oh,Orazio Nicolotti

doi:10.1007/s11356-021-13320-y

Abstract

Eleven piperazine-containing 1,3-diphenylprop-2-en-1-one derivatives (PC1-PC11) were evaluated for their inhibitory activities against monoamine oxidases (MAOs), cholinesterases (ChEs), and β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) with a view toward developing new treatments for neurological disorders. Compounds PC10 and PC11 remarkably inhibited MAO-B with IC50 values of 0.65 and 0.71 μM, respectively. Ten of the eleven compounds weakly inhibited AChE and BChE with > 50% of residual activities at 10 μM, although PC4 inhibited AChE by 56.6% (IC50 = 8.77 μM). Compound PC3 effectively inhibited BACE-1 (IC50 = 6.72 μM), and PC10 and PC11 moderately inhibited BACE-1 (IC50 =14.9 and 15.3 μM, respectively). Reversibility and kinetic studies showed that PC10 and PC11 were reversible and competitive inhibitors of MAO-B with Ki values of 0.63 ± 0.13 and 0.53 ± 0.068 μM, respectively. ADME predictions for lead compounds revealed that PC10 and PC11 have central nervous system (CNS) drug-likeness. Molecular docking simulations showed that fluorine atom and trifluoromethyl group on PC10 and PC11, respectively, interacted with the substrate cavity of the MAO-B active site. Our results suggested that PC10 and PC11 can be considered potential candidates for the treatment of neurological disorders such as Alzheimer’s disease and Parkinson’s disease.

Highlights

Of the heterogeneous and complex neurodegenerative disorders (NDDs) that largely affect the elderly, Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most prevalent and their pathogenesis have been attributed to a variety of genomic, epigenomic, and environmental factors (Van Bulck et al 2019)
ADME parameters including pharmacokinetic data and physical-chemical properties such as lipophilicity and water solubility of PC10 and PC11 were predicted in silico using free software available at http://www.swissadme.ch/ (Daina et al 2017)
Our findings show that the lead molecules PC4, PC10, and PC11 selectively inhibit monoamine oxidases (MAOs)-B at the submicromolar level and moderately inhibit AChE and BACE-1

Summary

Introduction

Of the heterogeneous and complex neurodegenerative disorders (NDDs) that largely affect the elderly, Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most prevalent and their pathogenesis have been attributed to a variety of genomic, epigenomic, and environmental factors (Van Bulck et al 2019). Environ Sci Pollut Res (2021) 28:38855–38866 molecular scaffolds have been designed to simultaneously target entities such as choline esterase (ChE), monoamine oxidases (MAOs), and β-site amyloid precursor protein cleaving enzyme 1 (β-secretase, BACE-1), to retard NDD progression (Zhang et al 2019). Piperazine is a heteromonocyclic, six-membered ring containing two secondary nitrogen atoms, and diazacycloalkane with a non-planar, flexible nature that can interact hydrophobically and by hydrogen bonding with target enzymes. The substitution of one or both nitrogen atoms in the piperazine ring system with various structural motifs can result in significant MAO-A, MAO-B, and acetylcholinesterase (AChE) inhibitions (Pettersson et al 2012; Kaya et al 2017; Kumar et al 2018; Özdemir et al 2020; Sağlık et al 2020; Jevtić et al 2020; Modh et al 2013; Sahin et al 2018)

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