MAO Inhibitory Activity of 2‐Arylbenzofurans versus 3‐Arylcoumarins: Synthesis, in vitro Study, and Docking Calculations

Abstract

Monoamine oxidase (MAO) is an important drug target for the treatment of neurological disorders. Several 3-arylcoumarin derivatives were previously described as interesting selective MAO-B inhibitors. Preserving the trans-stilbene structure, a series of 2-arylbenzofuran and corresponding 3-arylcoumarin derivatives were synthesized and evaluated as inhibitors of both MAO isoforms, MAO-A and MAO-B. In general, both types of derivatives were found to be selective MAO-B inhibitors, with IC50 values in the nano- to micromolar range. 5-Nitro-2-(4-methoxyphenyl)benzofuran (8) is the most active compound of the benzofuran series, presenting MAO-B selectivity and reversible inhibition (IC50 =140 nM). 3-(4'-Methoxyphenyl)-6-nitrocoumarin (15), with the same substitution pattern as that of compound 8, was found to be the most active MAO-B inhibitor of the coumarin series (IC50 =3 nM). However, 3-phenylcoumarin 14 showed activity in the same range (IC50 =6 nM), is reversible, and also severalfold more selective than compound 15. Docking experiments for the most active compounds into the MAO-B and MAO-A binding pockets highlighted different interactions between the derivative classes (2-arylbenzofurans and 3-arylcoumarins), and provided new information about the enzyme-inhibitor interaction and the potential therapeutic application of these scaffolds.

NH4PF6 as a Structural Modifier for Building a Robust Carbon‐Coated Natural Graphite Anode for Lithium‐Ion Batteries

“…However, the rest of the studied compounds showed no activity against human MAO‐A. Previous docking studies suggest a more limited binding inside the A isoform for similar types of coumarins 23. Both enzyme isoforms showed some different residues in the pocket that can have an important impact in ligand selectivity.…”

“…Since some of the synthesized derivatives exhibited good activity against hMAO‐B, we performed molecular docking calculations to predict the most stable poses of the ligands inside the protein binding site. To perform the modeling, we followed a similar protocol recently published by our research group22, 23 in which we used the crystallized structure of the hMAO‐B bound to 7‐(3‐chlorobenzyloxy)‐4‐carboxaldehyde‐coumarin ( c17 ) (PDB: 2V60) 24. A water molecule that establishes a hydrogen bond with the co‐crystallized ligand was retained in the pocket.…”

“…Both enzyme isoforms showed some different residues in the pocket that can have an important impact in ligand selectivity. Moreover, water molecules in the pocket can be important for ligand recognition, and their displacement could energetically limit the ligand–protein binding 23…”

Coumarin‐Rasagiline Hybrids as Potent and Selective hMAO‐B Inhibitors, Antioxidants, and Neuroprotective Agents

“…Different research groups, including ours, have shown that coumarin is a privileged scaffold for the rational discovery and development of new h MAO‐B inhibitors (Figure ) and antioxidant agents . In addition to being very potent and selective MAO inhibitors, several leads previously reported by the group have proven to be reversible inhibitors . Moreover, hybrid molecules bearing the coumarin scaffold have been already reported by the group .…”

Synthesis of Nitro-Substituted 2-Phenylbenzofurans Derivatives as Potential Human Monoamine Oxidase Inhibitors<strong> </strong>

“…8 Some benzofuran derivatives are also known as monoamine oxidase and 5-lipoxygenase inhibitors, antagonists of the angiotensin II receptor, blood coagulation factor Xa inhibitors, ligands of adenosine A1 receptor, 5,9 and more recently as MAO inhibitors. [10][11][12][13][14] In general, benzofurans described as MAO inhibitors have a higher selectivity to the MAO-B isoform. In our efforts to contribute to the development of novel compounds that may be useful in the treatment of neurodegenerative disorders such as PD or AD, we are focusing on 2-phenylbenzofuran derivatives.…”