Farzaneh Shabnam, Shahhosseini Soraya, Arefi Hadi, Daraei Bahram, Esfahanizadeh Marjan, Zarghi Afshin
Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Department of Toxicology, Faculty of Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Med Chem. 2018;14(7):652-659. doi: 10.2174/1573406414666180525133221.
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.
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.
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.
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).
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.
前列腺素是一类通过环氧化酶（COX）途径由花生四烯酸生物合成的二十碳烯酸。COX有两种亚型已得到充分证实：COX-1和COX-2。有证据支持环氧化酶-2在某些病理状况如炎症和癌症中起关键作用这一观点。
设计并合成了一组新的1,3-二苯基-3-（苯基氨基）丙-1-酮，以研究其COX-2抑制活性和对血小板聚集的抑制作用。
使用AutoDock vina软件进行对接研究。完成了体外COX-1和COX-2同工酶抑制研究以获得构效关系数据。通过比浊法测定体外抗血小板聚集活性。
体外COX抑制试验表明，除化合物8c外，所有衍生物均为选择性COX-2抑制剂，IC50值在有效的0.20 - 0.35 μM范围内，具有高COX-2选择性指数（SI）。分子建模和对接研究表明，合成的化合物具有与已知抑制剂SC-558相似的结合方式，SO2Me基团插入到COX-2二级口袋（Val523、Phe518、Ile517、Arg513和His90）中，中心α,β-不饱和羰基部分的C=O朝向COX-2结合位点（Tyr355和Arg120）的入口。
1,3-二苯基-3-（苯基氨基）丙-1-酮是新型COX-2抑制剂，对COX-2具有良好的抑制作用，对COX-1同工酶亲和力低。此外，我们的结果表明这些化合物中的大多数抑制花生四烯酸诱导的血小板聚集。
