Trimethoxylated Halogenated Chalcones as Dual Inhibitors of MAO-B and BACE-1 for the Treatment of Neurodegenerative Disorders

Six halogenated trimethoxy chalcone derivatives (CH1-CH6) were synthesized and spectrally characterized. The compounds were further evaluated for their inhibitory potential against monoamine oxidases (MAOs) and beta-secretase (BACE-1). Six compounds inhibited MAO-B more effectively than MAO-A, and the 2 ',3 ',4 '-methoxy moiety in CH4-CH6 was more effective for MAO-B inhibition than the 2 ',4 ',6 '-methoxy moiety in CH1-CH3. Compound CH5 most potently inhibited MAO-B, with an IC50 value of 0.46 mu M, followed by CH4 (IC50 = 0.84 mu M). In 2 ',3 ',4 '-methoxy derivatives (CH4-CH6), the order of inhibition was -Br in CH5 > -Cl in CH4 > -F in CH6 at the para-position in ring B of chalcone. CH4 and CH5 were selective for MAO-B, with selectivity index (SI) values of 15.1 and 31.3, respectively, over MAO-A. CH4 and CH5 moderately inhibited BACE-1 with IC50 values of 13.6 and 19.8 mu M, respectively. When CH4 and CH5 were assessed for their cell viability studies on the normal African Green Monkey kidney cell line (VERO) using MTT assays, it was noted that both compounds were found to be safe, and only a slightly toxic effect was observed in concentrations above 200 mu g/mL. CH4 and CH5 decreased reactive oxygen species (ROS) levels of VERO cells treated with H2O2, indicating both compounds retained protective effects on the cells by antioxidant activities. All compounds showed high blood brain barrier permeabilities analyzed by a parallel artificial membrane permeability assay (PAMPA). Molecular docking and ADME prediction of the lead compounds provided more insights into the rationale behind the binding and the CNS drug likeness. From non-test mutagenicity and cardiotoxicity studies, CH4 and CH5 were non-mutagenic and non-/weak-cardiotoxic. These results suggest that CH4 and CH5 could be considered candidates for the cure of neurological dysfunctions.

Automated summary

Six halogenated trimethoxy chalcone derivatives were synthesized and evaluated for their inhibitory potential against MAOs and BACE-1. Compounds CH4 and CH5 showed strong inhibition of MAO-B, exhibited protective effects on VERO cells, and had high blood brain barrier permeabilities.