Development of fluorinated methoxylated chalcones as selective monoamine oxidase-B inhibitors: Synthesis, biochemistry and molecular docking studies

• Synthesized methoxylated chalcones with fluoro and trifluoromethyl derivatives.
• Compounds showed reversible, selective and competitive MAO-B inhibition.
• Structure–activity relationship has been established.
• Key role of the steric effect at position 4 of the B ring of the chalcones was highlighted by docking studies.

A series of methoxylated chalcones with fluoro and trifluoromethyl derivatives were synthesized and investigated for their ability to inhibit human monoamine oxidase A and B. The chemical structures of the compounds have been characterized by means of their 1H NMR, 13C NMR, Mass spectroscopic datas and elemental analysis. The results demonstrate that these compounds are reversible and selective MAO-B inhibitors with a competitive mode of inhibition. The most potent compound (2E)-1-(4-methoxyphenyl)-3-[4-(trifluoromethyl)phenyl] prop-2-en-1-one showed the best activity and higher selectivity towards hMAO-B with Ki and SI values of 0.22 ± 0.01 μM and 0.05 comparable to that standard drug, Selegiline Ki and SI values were found as 0.33 ± 0.03 μM and 0.04, respectively. Molecular docking studies were carried out to further explain the in vitro results of the new compounds, and to identify the hypothetical binding mode for the compounds inside the inhibitor binding cavity of hMAO-B.

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