Fragment-based design, docking, synthesis, biological evaluation and structure-activity relationships of 2-benzo/benzisothiazolimino-5-aryliden-4-thiazolidinones as cycloxygenase/lipoxygenase inhibitors

被引:77
作者
Eleftheriou, Phaedra [2 ]
Geronikaki, Athina [1 ]
Hadjipavlou-Litina, Dimitra [1 ]
Vicini, Paola [3 ]
Tarasova, Olga A. [4 ]
Filimonov, Dmitry [4 ]
Poroikov, Vladimir [4 ]
Chaudhaery, Shailendra S. [5 ]
Roy, Kuldeep K. [5 ]
Saxena, Anil K. [5 ]
机构
[1] Aristotle Univ Thessaloniki, Dept Pharmaceut Chem, Sch Pharm, Thessaloniki 54124, Greece
[2] Alexander Technol Educ Inst Thessaloniki, Sch Hlth & Med Care, Dept Med Lab Studies, Thessaloniki 57400, Greece
[3] Univ Parma, Dipartimento Farmaceut, I-43124 Parma, Italy
[4] Rus Acad Med Sci, Inst Biomed Chem, Moscow 119121, Russia
[5] Cent Drug Res Inst, Lucknow 226001, Uttar Pradesh, India
关键词
Multi-target drugs; Inflammation; COX-1/2; inhibitors; Lipoxygenase inhibitors; Benzo/benzisothiazolidinones; Fragment-based drug design; ANTIMICROBIAL ACTIVITY; CRYSTAL-STRUCTURE; DUAL INHIBITORS; DRUG DISCOVERY; LIGAND DESIGN; CYCLOOXYGENASE-2; DERIVATIVES; MECHANISM; CANDIDATE; ACID;
D O I
10.1016/j.ejmech.2011.10.029
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Balanced modulation of several targets is one of the current strategies for the treatment of multi-factorial diseases. Based on the knowledge of inflammation mechanisms, it was inferred that the balanced inhibition of cyclooxygenase-1/cyclooxygenase-2/lipoxygenase might be a promising approach for treatment of such a multifactorial disease state as inflammation. Detection of fragments responsible for interaction with enzyme's binding site provides the basis for designing new molecules with increased affinity and selectivity. A new chemoinformatics approach was proposed and applied to create a fragment library that was used to design novel inhibitors of cycloxygenase-1/cycloxygenase-2/lipoxygenase enzymes. Potential binding sites were elucidated by docking. Synthesis of novel compounds, and the in vitro/in vivo biological testing confirmed the results of computational studies. The benzothiazolyl moiety was proved to be of great significance for developing more potent inhibitors. (C) 2011 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码:111 / 124
页数:14
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