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

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.