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

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

Volume: 14 Issue: 7

Author(s): Shabnam Farzaneh, Soraya Shahhosseini, Hadi Arefi, Bahram Daraei, Marjan Esfahanizadeh and Afshin Zarghi*

Affiliation:

• Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran,Iran

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

Abstract: 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-1-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 µM 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 SO2Me group was inserted into the COX-2 secondary pocket (Val523, Phe518, Ile517, Arg513 and His90) and C=O of the central α, β-unsaturated-carbonyl moiety was oriented toward the entrance to the COX-2 binding site (Tyr355 and Arg120).

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.

Cite this article as:

Farzaneh Shabnam , Shahhosseini Soraya , Arefi Hadi, Daraei Bahram , Esfahanizadeh Marjan and Zarghi Afshin *, Design, Synthesis and Biological Evaluation of New 1,3-diphenyl-3- (phenylamino)propan-1-ones as Selective Cyclooxygenase (COX-2) Inhibitors, Medicinal Chemistry 2018; 14 (7) . https://dx.doi.org/10.2174/1573406414666180525133221