Design, Synthesis, Biological Evaluation, and In Silico Study of Tetrahydropyridines as Prospective Monoamine Oxidase Inhibitors

Funding Sponsor

King Saud University

Author's Department

Chemistry Department

Fifth Author's Department

Chemistry Department

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https://doi.org/10.1002/open.202400516

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Obaid ur Rehman Khan Bilal Ahmad Khan Syeda Shamila Hamdani Saquib Jalil Hatem Tallima Peter A. Sidhom Khalid Elfaki Ibrahim Tarad Abalkhail Jamshed Iqbal Tamer Shoeib Mahmoud A.A. Ibrahim

Document Type

Research Article

Publication Title

Chemistryopen

Publication Date

10-1-2025

doi

10.1002/open.202400516

Abstract

The potentiality of monoamine oxidase (MAO) enzymes to break monoamine neurotransmitters makes them efficacious druggable targets. Molecules having MAO-A inhibition characteristics are utilized as antidepressants while molecules with MAO-B inhibition prospective are utilized to treat Parkinson's and Alzheimer's diseases. Herein, we have shown how the selective inhibition of both isozymes can be attained by varying the substitution of electron-withdrawing and donating groups on the phenyl rings of tetrahydropyridines, i. e., ethyl 1,2,6-triaryl-4-(arylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate (4 a–4 o). The structures of these piperidines (4 a–4 o) were unambiguously established by different spectro-analytical techniques, including 1H- and 13C-NMR. Among the synthesized compounds, compounds 4 l and 4 n were identified as the most promising inhibitors of MAO-A and MAO-B, with IC50 values of 0.40±0.05 and 1.01±0.03 μM, respectively, compared with positive controls, namely clorgyline and l-deprenyl, with IC50 values of 0.0045±0.0003 and 0.0196±0.001 μM, respectively. The binding interactions of the most potent derivatives within the binding pocket of the MAO-A and MAO-B enzymes were predicted by molecular docking studies. Binding mode analysis revealed the capacity of compounds 4 l and 4 n to exhibit a hydrogen bond with PHE177 of MAO-A and GLN206 of MAO-B, respectively.

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