Design, Synthesis and Biological Evaluation of New 1,3-diphenyl-3-(phenylamino)propan-1-ones as Selective Cyclooxygenase (COX-2) Inhibitors

作者：Farzaneh Shabnam; Shahhosseini Soraya; Arefi Hadi; Daraei Bahram; Esfahanizadeh Marj An; Zarghi Afshin^*

来源：Medicinal Chemistry, 2018, 14(7): 652-659.

DOI：10.2174/1573406414666180525133221

• Synthesis
• 1,3-diphenyl-3-(phenylamino)propan-1-ones
• selective COX-2 inhibitors
• platelet aggregation inhibitors
• molecular modeling

Background: Prostaglandins are a family of eicosanoids biosynthesized from arachidonic acid through cyclooxygenase (COX) pathway. Two isoforms of COX are well established: COX-1, COX-2. Evidence supports the notion that cyclooxygenase-2, plays a crucial role in some pathological conditions such as inflammation and cancer.
Objective: A new group of 1,3-diphenyl-3-(phenylamino)propan-l-ones was designed and synthesized to investigate for their COX-2 inhibitory activity and inhibition of platelet aggregation.
Method: Docking study was performed using AutoDock vina software. In vitro COX-1 and COX-2 isozyme inhibition studies were accomplished to obtain structure activity relationship data. The in vitro antiplatelet aggregation activity was determined by turbidimetric procedure.
Results: In vitro COX inhibition assay showed that except compound 8c, all derivatives were selective COX-2 inhibitors with IC50 values in the potent 0.20-0.35 1.1.M range with high COX-2 selectivity indexes (SI). Molecular modeling and docking studies indicated that synthesized compounds had a binding similar to that of the known inhibitor SC-558 and the SO2 Me group was inserted into the COX-2 secondary pocket (Va1(523), Phe(518), Ile(517), Arg(513) and His(90)) and C=0 of the central alpha, beta-unsaturated-carbonyl moiety was oriented toward the entrance to the COX-2 binding site (Tyr(355) and Arg(120)).
Conclusion: The 1,3-diphenyl-3-(phenylamino)propan-1-ones are novel COX-2 inhibitors with good COX-2 inhibitory and low affinity for COX-1 isoenzyme. Also our results demonstrated that majority of these compounds inhibited AA-induced platelet aggregation.

• 出版日期2018