Design, synthesis, and biological activity of 2-aroylbenzofuran-3-ols and 2-aroylbenzofuran derivatives. A new route towards hMAO-B inhibition

The crucial role of human monoamine oxidases (hMAOs), particularly the B isoform, in the pathogenesis of neurodegenerative diseases has been extensively studied. Alongside numerous other factors, the clinical use of hMAO-B inhibitors to alleviate symptoms of Parkinson’s disease is well-established. In order to develop novel hMAO-B inhibitors as potential candidates for the treatment of these conditions, we have designed and synthesized two libraries of compounds based on the 2-aroylbenzofuran-3-ol and the 2-aroylbenzofuran scaffolds. The hMAO inhibitory activity and selectivity of these compounds was thoroughly investigated. In general, the 2- aroylbenzofuran-3-ols were unable to inhibit hMAO isoforms. In contrast, 2-aroylbenzofuran derivatives acted as potent and selective hMAO-B inhibitors, showing IC50 values within the nanomolar range and as low as 8.2 nM. The best compounds exhibited broad safety ranges in human gingival fibroblasts (hGFs) and SH-SY5Y neuroblastoma cells. A preliminary evaluation of the compounds’ neuroprotective effects was conducted through the co-exposure of the cells to the neurotoxic agent 6-hydroxydopamine (6-OHDA) and the synthesized compounds, whose activity was comparable to that of (R)-(− )-deprenyl, the reference hMAO-B inhibitors. The characterization of the compounds was enriched with the in silico prediction of the drug-likeness of the most active compounds among the 2-aroyl benzofurans using the free web tool SwissADME. All compounds were predicted to have high gastrointestinal absorption and to permeate the blood-brain barrier and molecular modelling studies provided insights into the molecular mechanisms responsible for the high hMAO-B inhibitory potency and selectivity of 2-aroylbenzofurans.