Zarghi Afshin, Zebardast Tannaz, Hakimion Farinaz, Shirazi Farshad H, Rao P N Praveen, Knaus Edward E
Department of Pharmaceutical Chemistry and Toxicology, School of Pharmacy, Shaheed Beheshti University of Medical Sciences, Tehran, Iran.
Bioorg Med Chem. 2006 Oct 15;14(20):7044-50. doi: 10.1016/j.bmc.2006.06.022. Epub 2006 Jun 22.
A group of (E)-1,3-diphenylprop-2-en-1-one derivatives (chalcones) possessing a MeSO(2)NH, or N(3), COX-2 pharmacophore at the para-position of the C-1 phenyl ring were synthesized using a facile stereoselective Claisen-Schmidt condensation reaction. In vitro COX-1/COX-2 structure-activity relationships were determined by varying the substituents on the C-3 phenyl ring (4-H, 4-Me, 4-F, and 4-OMe). Among the 1,3-diphenylprop-2-en-1-ones possessing a C-1 para-MeSO(2)NH COX-2 pharmacophore, (E)-1-(4-methanesulfonamidophenyl)-3-(4-methylphenyl)prop-2-en-1-one (7b) was identified as a selective COX-2 inhibitor (COX-2 IC(50)=1.0 microM; selectivity index >100) that was less potent than the reference drug rofecoxib (COX-2 IC(50)=0.50 microM; SI>200). The corresponding 1,3-diphenylprop-2-en-1-one analogue possessing a C-1 para-N(3) COX-2 pharmacophore, (E)-1-(4-azidophenyl)-3-(4-methylphenyl)prop-2-en-1-one (7f), exhibited potent and selective COX-2 inhibition (COX-1 IC(50)=22.2 microM; COX-2 IC(50)=0.3 microM; SI=60). A molecular modeling study where 7b and 7f were docked in the binding site of COX-2 showed that the p-MeSO(2)NH and N(3) substituents on the C-1 phenyl ring are oriented in the vicinity of the COX-2 secondary pocket (His90, Arg513, Phe518, and Val523). The structure-activity data acquired indicate that the propenone moiety constitutes a suitable scaffold to design new acyclic 1,3-diphenylprop-2-en-1-ones with selective COX-1 or COX-2 inhibitory activity.
通过简便的立体选择性克莱森-施密特缩合反应，合成了一组在C-1苯环对位带有MeSO(2)NH或N(3)、COX-2药效基团的(E)-1,3-二苯基丙-2-烯-1-酮衍生物（查耳酮）。通过改变C-3苯环上的取代基（4-H、4-Me、4-F和4-OMe）来确定体外COX-1/COX-2构效关系。在具有C-1对位-MeSO(2)NH COX-2药效基团的1,3-二苯基丙-2-烯-1-酮中，(E)-1-(4-甲磺酰胺基苯基)-3-(4-甲基苯基)丙-2-烯-1-酮(7b)被鉴定为一种选择性COX-2抑制剂（COX-2 IC(50)=1.0微摩尔；选择性指数>100），其活性低于参考药物罗非昔布（COX-2 IC(50)=0.50微摩尔；SI>200）。相应的具有C-1对位-N(3) COX-2药效基团的1,3-二苯基丙-2-烯-1-酮类似物，(E)-1-(4-叠氮基苯基)-3-(4-甲基苯基)丙-2-烯-1-酮(7f)，表现出强效且选择性的COX-2抑制作用（COX-1 IC(50)=22.2微摩尔；COX-2 IC(50)=0.3微摩尔；SI=60）。一项将7b和7f对接至COX-2结合位点的分子模拟研究表明，C-1苯环上的对-MeSO(2)NH和N(3)取代基位于COX-2二级口袋（His90、Arg513、Phe518和Val523）附近。所获得的构效数据表明，丙烯酮部分构成了一个合适的骨架，可用于设计具有选择性COX-1或COX-2抑制活性的新型无环1,3-二苯基丙-2-烯-1-酮。
