Synthesis and three-dimensional qualitative structure selectivity relationship of 3,5-disubstituted-2,4-thiazolidinedione derivatives as COX2 inhibitors

被引:39
作者
Ali, Ahmed M.
Saber, Gamal E.
Mahfouz, Nadia M.
El-Gendy, Mahmoud A.
Radwan, Awwad A. [1 ]
Hamid, Mohamed A. -El.
机构
[1] Assiut Univ, Dept Organ Pharmaceut Chem, Fac Pharm, Assiut 71527, Egypt
[2] Assiut Univ, Dept Med Chem, Fac Pharm, Assiut, Egypt
[3] Ain Shams Univ, Dept Pharmaceut Chem, Fac Pharm, Cairo, Egypt
关键词
3D-QSSR; 2,4-thiazolidinediones; COX2; inhibitors; catalyst; dock6;
D O I
10.1007/BF02980259
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
In our effort for synthesis of selective COX2 inhibitors, certain new 2,4-thiazolidinedione derivatives were synthesized. It necessitates preparation of potassium salt of 2,4-thiazolidinedione 2, which condensed with intermediate 4a. The resulting 3-[2-(4-methylphenyl)-2-oxo-1-phenylethyl]-2,4-thiazolidinedione 8 was condensed with appropriate aldehyde to afford compounds 10a, 10i-I, 10o and 10p. Compounds (9a-I, 10a-n, 10p, 11 and 12) were obtained through the preparation of 5-arylmethylidene-2,4-thiazolidinediones 6a-p and reaction of its potassium salt 7a-p with compounds 4a, 4b, and 5. Some compounds displayed significant analgesic activity as compared to reference standards. The anti-inflammatory activity of the synthesized compounds revealed that intermediate 8 and compounds 9c, 10c and 10d showed good results. Compound 10c produced no significant mucosal injury. HipHop methodology of Catalyst program was used to build up hypothetical model of selective COX2 inhibitors followed by fitting the synthesized compounds to this model. Compounds 10c and 10d were suspected to be promising selective COX2 inhibitors. Also, compounds (6c, 8, 9a,c,d,k, 10a,c,d,k, 11 and 12) were docked into COX1 and COX2 X-ray structures, using DOCK6 program. Docking results suggested that several of these derivatives are active COX inhibitors with a significant preference for COX2.
引用
收藏
页码:1186 / 1204
页数:19
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