Heteroarylimino-4-thiazolidinones as inhibitors of cartilage degradation

2-Benzo[d]thiazolyl- and 2-benzo[d]isothiazolyl-imino-5-benzylidene-4-thiazolidinone derivatives were investigated as potential metalloproteinases (MMPs) inhibitors and evaluated for their antidegenerative activity on human chondrocyte cultures stimulated by IL-1β, using an experimental model that reproduces the mechanisms involved in osteoarthritic (OA) diseases. Cell viability, the amount of glycosaminoglycans (GAGs) and the production of nitric oxide (NO) were measured. The most potent compound, 5-(4-methoxy-benzylidene)-2-(benzo[d]isothiazol-3-ylimino)-thiazolidin-4-one (4b), a MMP-13 inhibitor at nanomolar concentration (IC50 = 0.036 μM), could be considered as a lead compound for the development of novel clinical agents, inhibitors of cartilage degradation, for the treatment of OA.

Interleukin-1 β (IL-1β), a cytokine produced by chondrocytes induces high levels of prostaglandins E2 (PGE2) and nitric oxide (NO), that has been shown to inhibit collagen and proteoglycans synthesis, increase susceptibility to injury by other oxidant (e.g. H2O2).Figure optionsDownload as PowerPoint slideResearch highlights
► New 4-hiazolidinones are inhibitors of MMPs and degenerative/inflammation mediators.
► Heteroarylimino-4-thiazolidinones are inhibitors of cartilage degradation.
► We found a benzisothiazolyliminothiazolidin-4-one as lead compound for OA treatment.