title: 1,2-Diaryl-2-hydroxyiminoethanones as dual COX-1 and β-amyloid aggregation inhibitors: biological evaluation and in silico study.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Mazandaran University of Medical Sciences, PO Box 48175-861, Sari, Iran.
authors.forename: Hamid
authors.initials: H
authors.lastname: Irannejad
authors.forename: Oya
authors.initials: O
authors.lastname: Unsal Tan
authors.forename: Keriman
authors.initials: K
authors.lastname: Ozadali
authors.forename: Sakineh
authors.initials: S
authors.lastname: Dadashpour
authors.forename: Tuba
authors.initials: T
authors.lastname: Tuylu Kucukkilinc
authors.forename: Nematollah
authors.initials: N
authors.lastname: Ahangar
authors.forename: Mahsa
authors.initials: M
authors.lastname: Ahmadnejad
authors.forename: Saeed
authors.initials: S
authors.lastname: Emami
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051545:Cyclooxygenase 1 / Q000276:immunology; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D007659:Ketones / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism; D066329:Protein Aggregates / Q000187:drug effects; D066263:Protein Aggregation, Pathological / Q000188:drug therapy / Q000378:metabolism; D012756:Sheep
chemical_list: D016229:Amyloid beta-Peptides; D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D007659:Ketones; D010446:Peptide Fragments; D066329:Protein Aggregates; C075222:amyloid beta-protein (1-42); D051545:Cyclooxygenase 1
keywords: 1,2-diarylethanones; conformational & docking study; molecular dynamic simulation; selective COX-1 inhibitor; β-amyloid aggregation