2-Benzisothiazolylimino-5-benzylidene-4-thiazolidinones as protective agents against cartilage destruction.
We report the synthesis, the antioxidant and the inhibitory activity (IC50) on metalloproteinases (MMPs) 3 and 13 of 2-benzo[d]isothiazolylimino-5-benzylidene-4-thiazolidinones. Their potential as protective agents in osteoarthritis (OA) was evaluated by biological assays on chondrocytes cultures, stimulated by IL-1β. The chondroprotective capability, related both to antioxidant activity and to inhibition of MMPs, was studied in vitro, by determining nitric oxide production and glycosaminoglycans release. Moreover, selected derivatives 1h and 1g was studied for nuclear factor kappaB (NF-κB) inhibition by Western Blot analysis and for MMP-3 protein release using ELISA test. The structure-activity relationship of tested compounds demonstrates a favorable effect of the para substitution on the 5-benzilydene ring. Compound 1g shows a potent and selective activity on MMP-3 versus MMP-13. Accordingly, 1g possesses high antioxidant effect, NO lowering and GAGs restoring capability and also reduces the production of MMPs and NF-κB expression. Thus 1g can be considered as new potential chondroprotective agents.
Department of Drug Sciences, University of Catania, V. le A. Doria 6, 95125 Catania, Italy. Electronic address: luciacrasci@alice.it.
Lucia
L
Crascì
Department of Pharmacy, University of Parma, Parco Area Delle Scienze 27/A, 43124 Parma, Italy.
Paola
P
Vicini
Department of Pharmacy, University of Parma, Parco Area Delle Scienze 27/A, 43124 Parma, Italy.
Matteo
M
Incerti
Department of Physiological Sciences, University of Catania, V. le A. Doria 6, 95125 Catania, Italy.
Venera
V
Cardile
Department of Surgery, University of Catania, V. le A. Doria 6, 95125 Catania, Italy.
Sergio
S
Avondo
Department of Drug Sciences, University of Catania, V. le A. Doria 6, 95125 Catania, Italy.
Annamaria
A
Panico
D002356:Cartilage / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D010003:Osteoarthritis / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D020011:Protective Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D053778:Thiazolidines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use
D020011:Protective Agents; D053778:Thiazolidines; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3
Chondroprotective activity; Glycosaminoglycans; Metalloproteinase-13; Metalloproteinase-3; ORAC; Thiazolidinones