1,2-Diaryl-2-hydroxyiminoethanones as Dual COX-1 and β-Amyloid Aggregation Inhibitors: Biological Evaluation and In Silico Study.

Irannejad, Hamid; Unsal Tan, Oya; Ozadali, Keriman; Dadashpour, Sakineh; Tuylu Kucukkilinc, Tuba; Ahangar, Nematollah; Ahmadnejad, Mahsa; Emami, Saeed

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 μ m, SI > 833). To evaluate their potential use against Alzheimer's disease, in vitro evaluation of β-amyloid fibril formation using A β(1-40) and A β(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.

INFLAMMATION treatment; DIARYL compounds synthesis; MOLECULAR docking; DRUG design; MOLECULAR dynamics; AMYLOID beta-protein

Chemical Biology & Drug Design, 2015, Vol 85, Issue 4, p494

1747-0277

Academic Journal

10.1111/cbdd.12435