Synthesis and molecular dynamic studies on 2-(benzisothiazolyl)-N-(4-oxo-2-aryl-thiazolidinyl)-propanamides as potent inhibitors of metalloproteinases

The matrix metalloproteinases (MMPs) are a large family of zinc dependant proteases with a central role in degradation and remodelling of the extracellular matrix (ECM). These enzymes are implicated in many pathological conditions, such as inflammation, cancer, Alzheimer’s disease and osteoarthritis (OA). The use of MMPs inhibitors, potent and selective, could represent an excellent strategy for the treatment of these pathologies.(1) In our previous study, 4-thiazolidinones have shown to possess anti-inflammatory and anti-degenerative properties.(2) In particular 2-benzisothiazolylimino-5-benzylidene-4-thiazolidinones inhibited MMP-3 and -13, the major MMPs involved in cartilage degradation in OA disease.(3) Among these 5-(4-methoxybenzylidene)-2-(benzisothiazol-2-ylimino)-thiazolidin-4-one proved to be the most potent and selective MMP-13 inhibitor (IC50 = 0.036 µM). Docking studies indicate a non-chelating zinc interaction mode.(4) On the basis of this considerations, we synthesized 2-(benzo[d]isothiazol-3-yl)-N-(4-oxo-2-arylthiazolidin-3-yl)propanamides (figure1), a novel class of potential antidegenerative multi–targeted drugs combining two pharmacophoric heterocycles and the propanoic chain of the well known antinflammatory profene drugs. Figure 1. 2-(benzo[d]isothiazol-3-yl)-N-(4-oxo-2-arylthiazolidin-3-yl)propanamides This study reports molecular dynamic interaction and inhibition activity (IC50) of 2-(benzo[d]isothiazol-3-yl)-N-(4-oxo-2-arylthiazolidin-3-yl) propanamides 1a–e, on MMP-9 and MMP-13, particularly involved in tissue degeneration.(5) The results show how the inclusion of hydrophilic, lipophilic, electron-withdrawing and donors groups, influences the interaction and inhibition towards MMP-9 and -13.