title: Design, synthesis and in vitro study of 5,6-diaryl-1,2,4-triazine-3-ylthioacetate derivatives as COX-2 and β-amyloid aggregation inhibitors.
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.
authors.affiliation: Student Research Committee, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Sakineh
authors.initials: S
authors.lastname: Dadashpour
authors.forename: Tuba
authors.initials: T
authors.lastname: Tuylu Kucukkilinc
authors.forename: Oya
authors.initials: O
authors.lastname: Unsal Tan
authors.forename: Keriman
authors.initials: K
authors.lastname: Ozadali
authors.forename: Hamid
authors.initials: H
authors.lastname: Irannejad
authors.forename: Saeed
authors.initials: S
authors.lastname: Emami
mesh_terms: D000085:Acetates / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010539:Permeability; D058225:Plaque, Amyloid; D066263:Protein Aggregation, Pathological; D055550:Protein Stability; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000085:Acetates; D016229:Amyloid beta-Peptides; D052246:Cyclooxygenase 2 Inhibitors; D014227:Triazines; C093444:1,2,4-triazine
keywords: 1,2,4-Triazine-3-ylthioacetate; Blood-brain barrier permeability; COX-2 inhibitor; Molecular docking; β-Amyloid aggregation