1, 2‐Diaryl‐2‐hydroxyiminoethanones as Dual COX‐1 and β‐Amyloid Aggregation Inhibitors: Biological Evaluation and In Silico Study. (11th October 2014)

• Record Type: Journal Article
• Authors: Irannejad, Hamid; Unsal Tan, Oya; Ozadali, Keriman; Dadashpour, Sakineh; Tuylu Kucukkilinc, Tuba; Ahangar, Nematollah; Ahmadnejad, Mahsa; Emami, Saeed
• Is Part Of: Chemical biology & drug design. Volume 85:Number 4(2015:Apr.)
• Page Start: 494
• Page End: 503
• Publication Date: 2014-10-11
• Subjects: Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12435
• Languages: English
• ISSNs: 1747-0277

Abstract

<abstract abstract-type="main" id="cbdd12435-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 <italic>in vitro</italic>, <italic> in vivo</italic>, and computational studies. The <italic>in vivo</italic> 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 <italic>in vitro </italic>COX‐1/COX‐2 evaluations revealed that 4‐methoxy derivative <bold>3</bold> had a high selective COX‐1 inhibitory activity (COX‐1, IC<sub>50</sub> = 0.12 <italic>μ</italic><sc>m</sc>, SI > 833). To evaluate their potential use against Alzheimer's disease, <italic>in vitro</italic> evaluation of <italic>β</italic>‐amyloid fibril formation using A<italic>β</italic><sub>(1–40)</sub> and A<italic>β</italic><sub>(1–42)</sub> peptides was performed. The evaluation of their antiaggregation ability gave impressive results and comparable to rifampicin and indomethacin. Conformational study of compound <bold>3</bold> 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.</p> </abstract>