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

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

Journal

International Journal of Molecular Sciences
ISSN: 1661-6596 , E-ISSN: 1422-0067

Output data

Year: 2025, Volume: 26, Number: 20, Article number : 10197, Pages count : DOI: 10.3390/ijms262010197

Authors

Petrou Anthi ¹ , Deruvo Caterina ² , Purgatorio Rosa ² , Lichitsky Boris ³ , Komogortsev Andrey N. ³ , Kartsev Victor G. ⁴ , de Candia Modesto ² , Catto Marco ² , Altomare Cosimo D. ² , Geronikaki Athina ¹

Affiliations

1	Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
2	Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, Italy
3	Zelinsky Institute of Organic Chemistry, Leninsky Prospect, 119991 Moscow, Russia
4	InterBioScreen Ltd., 119019 Moscow, Russia

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.

Petrou A. , Deruvo C. , Purgatorio R. , Lichitsky B. , Komogortsev A.N. , Kartsev V.G. , de Candia M. , Catto M. , Altomare C.D. , Geronikaki A.
Investigating Amphoteric 3,4′-Biscoumarin-Based ortho-[(Dialkylamino)methyl]phenols as Dual MAO and ChE Inhibitors
International Journal of Molecular Sciences. 2025. V.26. N20. 10197 . DOI: 10.3390/ijms262010197 WOS Scopus OpenAlex

Web of science:	WOS:001601679800001
Scopus:	2-s2.0-105020277003
OpenAlex:	W4415370597

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