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

Phaedra Eleftheriou; Athina Geronikaki; Dimitra Hadjipavlou-Litina; Paola Vicini; Olga Filz; Dmitry Filimonov; Vladimir Poroikov; Shailendra S Chaudhaery; Kuldeep K Roy; Anil K Saxena

doi:10.1016/j.ejmech.2011.10.029

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

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

Authors

Phaedra Eleftheriou¹, Athina Geronikaki, Dimitra Hadjipavlou-Litina, Paola Vicini, Olga Filz, Dmitry Filimonov, Vladimir Poroikov, Shailendra S Chaudhaery, Kuldeep K Roy, Anil K Saxena

Affiliation

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

PMID: 22119153
DOI: 10.1016/j.ejmech.2011.10.029

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.

MeSH terms

Animals
Anti-Inflammatory Agents / chemical synthesis
Anti-Inflammatory Agents / chemistry
Anti-Inflammatory Agents / metabolism
Anti-Inflammatory Agents / pharmacology
Catalytic Domain
Cyclooxygenase 1 / chemistry
Cyclooxygenase 1 / metabolism*
Cyclooxygenase 2 / chemistry
Cyclooxygenase 2 / metabolism*
Cyclooxygenase Inhibitors / chemical synthesis
Cyclooxygenase Inhibitors / chemistry
Cyclooxygenase Inhibitors / metabolism
Cyclooxygenase Inhibitors / pharmacology
Drug Design*
Edema / chemically induced
Edema / drug therapy
Female
Lipoxygenase / chemistry
Lipoxygenase / metabolism*
Lipoxygenase Inhibitors / chemical synthesis
Lipoxygenase Inhibitors / chemistry
Lipoxygenase Inhibitors / metabolism
Lipoxygenase Inhibitors / pharmacology
Male
Mice
Models, Molecular
Structure-Activity Relationship
Thiazolidines / chemical synthesis
Thiazolidines / chemistry*
Thiazolidines / metabolism
Thiazolidines / pharmacology*

Substances

Anti-Inflammatory Agents
Cyclooxygenase Inhibitors
Lipoxygenase Inhibitors
Thiazolidines
Lipoxygenase
Cyclooxygenase 1
Cyclooxygenase 2