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

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 IC values in the low micro or nanomolar range. The 2-(2'-bromophenyl)-5-methylbenzofuran () was the most active compound identified (IC = 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.

Monoamine oxidase‐B inhibitors as potential neurotherapeutic agents: An overview and update

“…In another study on benzofurans, Delogu et al designed a library of 2‐phenylbenzofuran derivatives ( 9a ‐ l ) by introducing a bromine substituent in the 2‐phenyl ring and a methyl group at the positions 5 to 7 in the benzofuran moiety (Figure ). Most of compounds preferentially inhibited hMAO‐B in a reversible manner, with IC 50 values in micromolar to submicromolar range (SI = 7‐400).…”

“…The results demonstrated that the compounds exhibited moderate to good MAO-B inhibitory activity in the micromolar to submicromolar range with reversible and competitive modeF I G U R E 1 6 2-Arylidenebenzofuran-3(2H)-ones (8a-t) 153. hMAO, human monoamine oxidase; SI, selectivity index F I G U R E 1 7 2-Arylbenzofurans (9a-l) 154. hMAO, human monoamine oxidase; SI, selectivity index of inhibition.…”

Structural Insight of New Butyrylcholinesterase Inhibitors Based on Benzylbenzofuran Scaffold

“…In our recent studies, we reported that 2-phenylbenzofuran derivatives display promising enzymatic inhibition properties against BChE [ 8 , 9 , 10 ] and monoamine oxidase (MAO) [ 11 , 12 , 13 ] enzymes. BChE plays a key role in the progression of Alzheimer’s disease (AD), a neurodegenerative disorder.…”

Construction of Diverse Dihydrodibenzofuranones by Migration/Intramolecular Arylation of Iodonium Ylides

“…2 They also display pharmacological properties such as selective inhibitors of the butyrylcholinesterase enzyme (BChE) for Alzheimer's disease, 3 stimulation of neurite outgrowth of NGF-mediated PC12-cells, 4 streptococcus mutans sortase A, 5 and monoamine oxidase (MAO). 6 They are also used as building blocks for the synthesis of biologically active natural products and functional materials. 7 Among these, dihydrodibenzofuranone scaffolds were also isolated in nature ( Figure 1) and they exhibited broad biological activities.…”