Sakineh Dadashpour, Tuba Tuylu Kucukkilinc, Oya Unsal Tan
Mar 1, 2015
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Influential Citations
26
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Quality indicators
Journal
Archiv der Pharmazie
Abstract
In order to find novel cyclooxygenase (COX)‐2 inhibitors for treating inflammatory‐based diseases such as Alzheimer's disease (AD), an ethyl carboxylate side chain was added to 5‐(4‐chlorophenyl)‐6‐(4‐(methylsulfonyl)phenyl)‐3‐(methylthio)‐1,2,4‐triazine (lead compound II) to maintain residual inhibition of COX‐1 through interacting with Arg120. A preliminary molecular docking study on both the COX‐1/COX‐2 active sites truly confirmed our hypothesis. Accordingly, a series of ethyl 5,6‐diaryl‐1,2,4‐triazine‐3‐ylthioacetate derivatives were synthesized and their chemical structures were confirmed by NMR, IR and MS spectra. Further in vitro COX‐1/COX‐2 evaluations revealed that compound 6c (COX‐2 IC50 = 10.1 μM, COX‐1 IC50 = 88.8 μM) is the most selective COX‐2 inhibitor while maintaining residual inhibition of COX‐1. In order to evaluate their potential use against AD, an in vitro evaluation of β‐amyloid fibril formation was performed. The results indicated that the prototype compounds 6 are effective β‐amyloid destabilizing agents while compound 6c could inhibit 94% of the β‐amyloid fibril formation after 48 h. Finally, the in silico assessment results of their blood–brain barrier permeability were satisfactory.