Synthesis and biological evaluation of N-difluoromethyl-1,2-dihydropyrid-2-one acetic acid regioisomers: Dual Inhibitors of cyclooxygenases and 5-lipoxygenase

文献类型： 外文期刊

第一作者： Yu, Gang

作者： Yu, Gang;Chowdhury, Morshed A.;Abdellatif, Khaled R. A.;Dong, Ying;Das, Dipankar;Velazquez, Carlos A.;Suresh, Mavanur R.;Knaus, Edward E.;Yu, Gang;Rao, P. N. Praveen

作者机构：

关键词： NSAIDs;Acetic acids;Regioisomers;N-Difluoromethyl-1,2-dihydropyrid-2-one pharmacophore;Cyclooxygenase isozyme and 5-lipoxygenase inhibition;Molecular modeling

期刊名称：BIOORGANIC & MEDICINAL CHEMISTRY LETTERS （ 影响因子：2.823； 五年影响因子：2.677 ）

ISSN： 0960-894X

年卷期： 2010 年 20 卷 7 期

页码：

收录情况： SCI

摘要： A new group of acetic acid (7a-c, R(1) = H), and propionic acid (7d-f, R(1) = Me), regioisomers wherein a N-difluoromethyl-1,2-dihydropyrid-2-one moiety is attached via its C-3, C-4, and C-5 position was synthesized. This group of compounds exhibited a more potent inhibition, and hence selectivity, for the cyclooxygenase-2 (COX-2) relative to the COX-1 isozyme. Attachment of the N-difluoromethyl-1, 2-dihydropyrid-2-one ring system to an acetic acid, or propionic acid, moiety confers potent 5-LOX inhibitory activity, that is, absent in traditional arylacetic acid NSAIDs. 2-(1-Difluoromethyl-2-oxo-1,2-dihydropyridin-5-yl) acetic acid (7c) exhibited the best combination of dual COX-2 and 5-LOX inhibitory activities. Molecular modeling (docking) studies showed that the highly electronegative CHF2 substituent present in 7c, that showed a modest selectivity for the COX-2 isozyme, is oriented within the secondary pocket (Val523) present in COX-2 similar to the sulfonamide (SO(2)NH(2)) COX-2 pharmacophore present in celecoxib, and that the N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore is oriented close to the region containing the LOX enzyme catalytic iron (His361, His366, and His545). Accordingly, the N-difluoromethyl-1,2-dihyrdopyrid-2-one moiety possesses properties suitable for the design of dual COX-2/5LOX inhibitory drugs. (C) 2010 Elsevier Ltd. All rights reserved.

分类号：

  • 相关文献

[1]Phenylacetic acid regioisomers possessing a N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore: Evaluation as dual inhibitors of cyclooxygenases and 5-lipoxygenase with anti-inflammatory activity. Yu, Gang,Chowdhury, Morshed A.,Abdellatif, Khaled R. A.,Dong, Ying,Das, Dipankar,Velazquez, Carlos A.,Suresh, Mavanur R.,Knaus, Edward E.,Yu, Gang,Rao, P. N. Praveen. 2010

[2]Identification of regioisomers of methylated kaempferol and quercetin by ultra high performance liquid chromatography quadrupole time-of-flight (UHPLC-QTOF) tandem mass spectrometry combined with diagnostic fragmentation pattern analysis. Ma, Chengying,Lv, Haipeng,Zhang, Xinzhong,Chen, Zongmao,Shi, Jiang,Lin, Zhi,Lu, Meiling.

[3]Study on Interaction between Coomassie Brilliant Blue G-250 and Bovine Serum Albumin by Fluorescence Spectroscopy and Molecular Modeling. Wang Yong-gang,Yang Guang-rui,Leng Fei-fan,Ma Jian-zhong,Ma Xue-qing,Wang Xiao-li. 2017

[4]Study on the interaction between cyanobacteria FBP/SBPase and metal ions. Sun, Yao,Liao, Xun,Li, Ding,Feng, Lingling,Wang, Xiaofeng,Jin, Jing,Yi, Fan,Zhou, Li,Wan, Jian,Li, Jun.

[5]Study on inclusion complexation between plant growth regulator 6-benzylaminopurine and beta-cyclodextrin: Preparation, characterization and molecular modeling. Ge, Xia,He, Jiang,Yang, Ying,Qi, Fengming,Lu, Ruihua,Huang, Lizhen,Yao, Xiaojun,Huang, Zheng. 2011

[6]Identification of an intraspecific alarm pheromone and two conserved odorant-binding proteins associated with (E)-beta-farnesene perception in aphid Rhopalosiphum padi. Xue, Wenxin,Jiang, Xin,Zhang, Yong,Yu, Wenjuan,Jiang, Shanshan,Sun, Jingrun,Chen, Julian,Duan, Hongxia. 2017

[7]Inclusion of quinestrol and 2,6-di-O-methyl-beta-cyclodextrin: Preparation, characterization, and inclusion mode. Ouyang, Can-Bin,Liu, Xiao-Hui,Liu, Qi,Yuan, Hao-Liang. 2013

[8]Inclusion complexation of chloropropham with beta-cyclodextrin: Preparation, characterization and molecular modeling. Ge, Xia,He, Jiang,Qi, Fengming,Yang, Ying,Lu, Ruihua,Huang, Lizhen,Ge, Xia,Huang, Zheng. 2011

[9]Combretastatin A-4 and Derivatives: Potential Fungicides Targeting Fungal Tubulin. Zhao, Lei,Zhou, Jiu-jiu,Pang, Wan,Kai, Zhen-peng,Wu, Fan-hong,Yan, Xiao-jing,Wu, Fan-hong.

[10]Quercitrin, an Inhibitor of Sortase A, Interferes with the Adhesion of Staphylococcal aureus. Liu, Bingrun,Chen, Fuguang,Bi, Chongwei,Zhong, Xiaobo,Cai, Hongjun,Wang, Dacheng,Chen, Fuguang,Wang, Lin,Deng, Xuming,Niu, Xiaodi.

作者其他论文 更多>>

微信小程序