Abstract
A series of benzo[b]thiophen-3-ols were synthesised and investigated as potential human monoamine oxidase (hMAO) inhibitors in vitro as well as ex vivo in rat cortex synaptosomes by means of evaluation of 3,4-dihydroxyphenylacetic acid/dopamine (DOPAC/DA) ratio and lactate dehydrogenase (LDH) activity. Most of these compounds possessed high selectivity for the MAO-B isoform and a discrete antioxidant and chelating potential. Molecular docking studies of all the compounds underscored potential binding site interactions suitable for MAO inhibition activity, and suggested structural requirements to further improve the activity of this scaffold by chemical modification of the aryl substituents. Starting from this heterocyclic nucleus, novel lead compounds for the treatment of neurodegenerative disease could be developed.
Highlights
Monoamine oxidases (MAOs; EC 1.4.3.4) are mitochondrial bound flavoenzymes, which catalyse the oxidative degradation of amines
In the light of the above, it may be concluded that electron donor groups improve inhibitory activity towards human monoamine oxidase (hMAO)-B when they are substituted on the meta- and para-positions
The data show that when the substituent changed from fluoro to chloro and to bromo, there was an increment of inhibitory activity and selectivity towards hMAO-B, according to the increased size and reduced electronegativity of the halogen, with the best inhibition and selectivity shown by compound PM12 (IC50 hMAO-B 1⁄4 0.35 mM; selectivity index (SI) 1⁄4 180)
Summary
Monoamine oxidases (MAOs; EC 1.4.3.4) are mitochondrial bound flavoenzymes, which catalyse the oxidative degradation of amines. The abnormal expression or increased activity of hMAOs may lead to the excessive production of H2O2 that can expose cells to oxidative damage In this respect, H2O2 participates in the Fenton reaction[6] and reacts with certain cations such as Cuþ and/or Fe2þ which leads to reactive the formation of oxygen species (ROS). Other important differences among these scaffolds are the isosteric replacement of the oxygen atom of aurones with sulphur and the presence of 1,3-diketonic system that, via keto-enol tautomerism, generates the corresponding chalcone while possessing the potential for metal chelation[20] This is a very interesting aspect and provides the possibility to obtain multi-target-directed drugs in the light of the evidence that some cations may contribute to neurodegeneration in CNS tissues. All the compounds were analysed by molecular modelling to better corroborate the biological data and to further determine which tautomer was responsible for the observed biological activity
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