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Eur J Med Chem. 2012 Jan;47(1):111-24. doi: 10.1016/j.ejmech.2011.10.029. Epub 2011 Oct 25.

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

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1
Department of Medical Laboratory Studies, School of Health and Medical Care, Alexander Technological Education Institute of Thessaloniki, Thessaloniki 57400, Greece.

Abstract

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.

PMID:
22119153
DOI:
10.1016/j.ejmech.2011.10.029
[Indexed for MEDLINE]

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