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

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.

A new statistical method was proposed and applied to identify the fragments involved in the inhibition of COX-1, COX-2 and LOX enzymes. The further chemicals synthesis of designed compounds and both in vitro and in vivo biological testing confirmed the results of computational modelling.Figure optionsDownload as PowerPoint slideHighlights
► Application of Fragment-Based Drug Design (FBDD) for multi-target drug design.
► Successful use of FBDD for development of COX1/2-LOX inhibitors.
► Confirmation of FBDD results by synthesis, in vitro/in vivo biological testing.
► Benzothiazolyl scaffold is important for inhibition of all three enzymes.