Investigating Amphoteric 3,4′-Biscoumarin-Based ortho-[(Dialkylamino)methyl]phenols as Dual MAO and ChE Inhibitors

TL;DR

This paper investigates new amphoteric compounds that can inhibit enzymes linked to neurodegenerative diseases, showing potential for drug development.

Contribution

The study identifies new phenolic Mannich bases with dual inhibition of MAO-A and AChE, offering potential for neurodegenerative disease treatment.

Findings

Five compounds showed moderate inhibition of human MAO-A with IC50s in the single-digit micromolar range.

Compound 3c also inhibited human AChE with an IC50 of 4.27 µM.

Molecular docking and chemoinformatic analysis confirmed binding modes and drug-likeness properties.

Abstract

Nineteen previously and newly synthesized amphoteric 8-[(dialkylamino)methyl]-7-hydroxy-4-(2-oxo-2H-chromen-3-yl)-2H-chromen-2-ones were assayed as inhibitors of monoamine oxidases (MAO-A and B) and cholinesterases (AChE and BChE). Five of the tested compounds (2b, 2c, 3c, 5b, and 5c), namely those bearing the less bulky alkyls in the Mannich base 8-CH2NR2 (R = Me, Et) and the halogens (Cl, Br) at C6 of the 4-coumarin-3-yl moiety, showed moderate inhibitory potencies toward human MAO-A in the single-digit micromolar range (IC50s from 1.49 to 3.04 µM). In particular, the 6′-Cl derivatives 2b and 5b proved to be reversible competitive inhibitors of human MAO-A with Ki values of 0.272 and 0.326 µM. Among the tested compounds, 3c proved to also be a moderate inhibitor of human AChE (IC50 4.27 µM). Molecular docking calculations suggested binding modes of the most active compounds to MAO-A and AChE binding sites consistent enough with the experimental data. Chemoinformatic tools suggest for the most active compounds, including the dual MAO-A/AChE inhibitor 3c, full compliance with Lipinski’s rule of five, high probability of gastrointestinal absorption, but low blood–brain barrier (BBB) permeability. While further efforts are required to improve their CNS distribution, herein new phenolic Mannich bases have been identified that may have potential for treating neurodegenerative syndromes.

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