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.

Graphical abstractA 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 full-size imageDownload 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.