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.

Molecular Docking and Structure-Based Drug Design Strategies

“…Recently, a series of selective COX-2 inhibitors acting as β-amyloid aggregation blockers was discovered via molecular docking [224]. Based on the structure of a diaryltriazine lead (compound 11, Figure 16), a series of derivatives was designed and docked into the active site of both COX-1 (PDB 3N8Z, 2.90 Å) and COX-2 (PDB 3NT1, 1.73 Å) (Figure 17) using AutoDock4.2.…”

Structure-based design, synthesis, molecular docking study and biological evaluation of 1,2,4-triazine derivatives acting as COX/15-LOX inhibitors with anti-oxidant activities

“…It has been reported that 1,2,4-triazine heterocyclic compounds with diaryl substituent (2) are effective COX-2 inhibitors 17,18 . Some experiments have reported structures in which the sulfonyl moiety on the aromatic ring is missing (3) [25][26][27] .…”

“…In contrast with the traditional NSAIDs which belong to different categories of chemical structures, selective COX-2 inhibitors can be classified into three groups ( Figure 1): (1) diaryl ethers with methanesulfonamide at position-2 of one ring, Nemisulide and CGP-28237 can be considered as lead compounds in this class 8 ; (2) trans-stilbenoids, such as resveratrol, a natural product found in grapes and other food products 9 ; (3) heterocyclic systems (such as 1,2,4 triazole 10,11 , imidazole 12 , pyrazol 13 , quinoline 14 , indol 15 , pyrimidine 16 , 1,2,4-triazine 17,18 ) with adjacent diaryl containing sulfamoyl (SO 2 NH 2 ) or methylsulfonyl (SO 2 Me) substitution at position-4 of one ring which exist in celecoxib, SC-558 and etoricoxib.…”

A crystallographic and theoretical study of an (E)-2-Hydroxyiminoethanone derivative: prediction of cyclooxygenase inhibition selectivity of stilbenoids by MM-PBSA and the role of atomic charge

“…Therefore, selectivity in the inhibition of COX isoforms is very important. One of the main factors influencing COX inhibition selectivity is the conformation of the inhibitor and its conformational flexibility (Irannejad et al, 2015). Only a few studies have been reported in the literature which consider the conformation of the inhibitor and its selectivity towards COX inhibition.…”

“…Recently, we unexpectedly discovered that a 2-hydroxyiminoethanone derivative, (E)-OXM, behaves as a highly selective COX-1 inhibitor (IC50 COX-1= 0.12 µM, IC50 COX-2 >100 µM, SI >833). This molecule also contains a sulfonylmethyl group which is a COX-2 selective pharmacophoric element ( Figure 1) (Irannejad, et al, 2015). In the same report, a preliminary computational study was performed to compare two states of the molecule, either when rigid or flexible, for docking.…”