Replacement of Chalcone-Ethers with Chalcone-Thioethers as Potent and Highly Selective Monoamine Oxidase-B Inhibitors and Their Protein-Ligand Interactions.

Bijo Mathew,Mohamed A Abdelgawad,T M Rangarajan,Githa Elizabeth Mathew,Mahmoud E S Soliman,Clement Agoni,Hoon Kim,Jong Min Oh,Lekshmi R Nath,Ahmed Khames

doi:10.3390/ph14111148

Abstract

To develop new potent and highly selective MAO-B inhibitors from chalcone-thioethers, eleven chalcones-thioethers were synthesized and their monoamine oxidase (MAO) inhibition, kinetics, reversibility, and cytotoxicity of lead compounds were analyzed. Molecular dynamics were carried out to investigate the interactions. Compound TM8 showed potent inhibitory activity against MAO-B, with an IC50 value of 0.010 µM, followed by TM1, TM2, TM7, and TM10 (IC50 = 0.017, 0.021, 0.023, and 0.026 µM, respectively). Interestingly, TM8 had an extremely high selectivity index (SI; 4860) for MAO-B. Reversibility and kinetic experiments showed that TM8 and TM1 were reversible and competitive inhibitors of MAO-B with Ki values of 0.0031 ± 0.0013 and 0.011± 0.001 µM, respectively. Both TM1 and TM8 were non-toxic to Vero cells with IC50 values of 241.8 and 116.3 µg/mL (i.e., 947.7 and 402.4 µM), respectively, and at these IC50 values, both significantly reduced reactive oxygen species (ROS) levels. TM1 and TM8 showed high blood-brain barrier permeabilities in the parallel artificial membrane permeability assay. Molecular dynamics studies were conducted to investigate interactions between TM1 and TM8 and the active site of MAO-B. Conclusively, TM8 and TM1 are potent and highly selective MAO-B inhibitors with little toxicity and good ROS scavenging abilities and it is suggested that both are attractive prospective candidates for the treatment of neurological disorders.

Highlights

IntroductionOver ten million people worldwide suffer from PD, which places an onerous responsibility on the medical community to develop an effective therapy [2]
Current treatment strategies center on enhancing dopamine-like activities monoamine oxidase (MAO)-B inhibitors, agopear to be focused on theusing identification of non-dopaminergic candidatesdopamine like glutamate nists, and catechol-O-methyltransferase (COMT) inhibitors, whereas developmental efforts antagonists and anticholinergic drugs [4]
We report aaa series series of chalcone-thioether derivatives, which were prepared andevaluevalevaluated for their inhibitory activities, cytotoxicities, and effect on evaluated for their inhibitory activities, cytotoxicities, and effect ated for inhibitory activities, cytotoxicities, and and effect on reactive uated fortheir their inhibitory activities, cytotoxicities, effect onon rereactive oxygen species (ROS)

Summary

Introduction

Over ten million people worldwide suffer from PD, which places an onerous responsibility on the medical community to develop an effective therapy [2]. This motor system disruption caused by the extensive degeneration the dopaminergic neurons, which leads. Current treatment strategies center on enhancing dopability on the medical community to develop an effective therapy [2] This motor system mine-like activities oxidase (MAO)-B dopamine agonists, disruption is causedusing by themonoamine extensive degeneration of the inhibitors, dopaminergic neurons, which and catechol-O-methyltransferase (COMT). Current treatment strategies center on enhancing dopamine-like activities monoamine oxidase (MAO)-B inhibitors, agopear to be focused on theusing identification of non-dopaminergic candidatesdopamine like glutamate nists, and catechol-O-methyltransferase (COMT) inhibitors, whereas developmental efforts antagonists and anticholinergic drugs [4]

Methods

Discussion

Conclusion