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1,2‐Diaryl‐2‐hydroxyiminoethanones as Dual COX ‐1 and β ‐Amyloid Aggregation Inhibitors: Biological Evaluation and In Silico Study
Author(s) -
Irannejad Hamid,
Unsal Tan Oya,
Ozadali Keriman,
Dadashpour Sakineh,
Tuylu Kucukkilinc Tuba,
Ahangar Nematollah,
Ahmadnejad Mahsa,
Emami Saeed
Publication year - 2015
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12435
Subject(s) - pharmacophore , in silico , in vivo , chemistry , in vitro , pharmacology , docking (animal) , amyloid (mycology) , biochemistry , stereochemistry , biology , medicine , inorganic chemistry , microbiology and biotechnology , nursing , gene
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, IC 50 = 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.