MAO inhibitory activity of bromo-2-phenylbenzofurans: synthesis, in vitro study, and docking calculations

Medchemcomm. 2017 Jul 7;8(9):1788-1796. doi: 10.1039/c7md00311k.

G L Delogu ¹, F Pintus ¹, L Mayán ² ³, M J Matos ⁴, S Vilar ⁴ ⁵, J Munín ² ⁴, J A Fontenla ³, G Hripcsak ⁵, F Borges ⁶, D Viña ²

Affiliations

1 Department of Life Sciences and Environment - Section of Pharmaceutical Sciences - University of Cagliari, 09124 Cagliari, Italy. Email: [email protected].
2 Department of Pharmacology - CIMUS University of Santiago de Compostela Avda Barcelona s/n, Campus Vida, 15782 Santiago de Compostela, Spain. Email: [email protected].
3 Department of Pharmacology, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
4 Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
5 Department of Biomedical Informatics, Columbia University, Medical Center of New York, 10032 New York, USA.
6 CIQUP/Department of Chemistry and Biochemistry, University of Porto, 4169-007, Portugal.

PMID: 30108888 DOI: 10.1039/c7md00311k

Abstract

Monoamine Oxidase (MAO) is an enzyme responsible for metabolism of monoamine neurotransmitters which play an important role in brain development and function. This enzyme exists in two isoforms, and it has been demonstrated that MAO-B activity, but not MAO-A activity, increases with aging. MAO inhibitors show clinical value because besides the monoamine level regulation they reduce the formation of by-products of the MAO catalytic cycle, which are toxic to the brain. A series of 2-phenylbenzofuran derivatives was designed, synthesized and evaluated against hMAO-A and hMAO-B Enzymes. A bromine substituent was introduced in the 2-phenyl ring, whereas position 5 or 7 of the benzofuran moiety was substituted with a methyl group. Most of the tested compounds inhibited preferentially MAO-B in a reversible manner, with IC₅₀ values in the low micro or nanomolar range. The 2-(2'-bromophenyl)-5-methylbenzofuran (5) was the most active compound identified (IC₅₀ = 0.20 μM). In addition, none of the studied compounds showed cytotoxic activity against the human neuroblastoma cell line SH-SY5Y. Molecular docking simulations were used to explain the observed hMAO-B structure-activity relationship for this type of compounds.

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