To find out new agents for treating inflammatory-involved diseases such as Alzheimer's disease, a series of 1,2-diaryl-2-hydroxyiminoethanones containing vicinal diaryl pharmacophore of COX inhibitors were tested by a set of in vitro, in vivo, and computational studies. The in vivo study of compounds indicated their prominent anti-inflammatory ability at the doses of 10 and 20 mg/kg comparable to celecoxib (10 mg/kg). Further in vitro COX-1/COX-2 evaluations revealed that 4-methoxy derivative 3 had a high selective COX-1 inhibitory activity (COX-1, IC50=0.12 μm, SI>833). To evaluate their potential use against Alzheimer's disease, in vitro evaluation of β-amyloid fibril formation using Aβ(1-40) and Aβ(1-42) peptides was performed. The evaluation of their antiaggregation ability gave impressive results and comparable to rifampicin and indomethacin. Conformational study of compound 3 and subsequent docking of its restrained analogs on both active sites of COX-1 and COX-2 could provide a proof of its COX-1 selectivity as well as molecular dynamic simulation could elucidate and give more insight into the amyloid disaggregation mechanisms leading to rational design of inhibitors.
Keywords: 1,2-diarylethanones; conformational & docking study; molecular dynamic simulation; selective COX-1 inhibitor; β-amyloid aggregation.
© 2014 John Wiley & Sons A/S.