Abstract
New derivatives of N-benzo[d]isothiazol-3-yl-benzamidine 6 a were synthesized as nonacidic anti-inflammatory/antidegenerative agents. We investigated the influence of the amidines 6 a-j on the production of NO, PGE(2), MMP-3, COX-2, ROS, and GAGs, key molecules involved in cartilage destruction in osteoarthritic diseases. The antidegenerative properties of the novel designed derivatives 6 b-j were improved with respect to N-benzo[d]isothiazol-3-yl-benzamidine 6 a. All of the compounds 6 a-j promoted the reduction of most of the IL-1beta-induced harmful effects. Derivatives 6 d, 6 h, and 6 j were the most potent of all the tested compounds, particularly in the human chondrocyte culture model.
MeSH terms
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Amidines / chemistry*
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Anti-Inflammatory Agents / chemical synthesis
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Anti-Inflammatory Agents / pharmacology
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Anti-Inflammatory Agents / therapeutic use*
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Benzamidines / chemical synthesis
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Benzamidines / pharmacology*
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Cartilage / drug effects*
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Cartilage / metabolism
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Cells, Cultured
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Chondrocytes / drug effects*
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Chondrocytes / metabolism
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Cyclooxygenase 2 / metabolism
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Glycosaminoglycans / metabolism
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Humans
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Interleukin-1beta / pharmacology*
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Matrix Metalloproteinase 3 / metabolism
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Nitric Oxide / metabolism
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Osteoarthritis / drug therapy*
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Protective Agents / chemical synthesis
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Protective Agents / pharmacology
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Protective Agents / therapeutic use*
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Reactive Oxygen Species / metabolism
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Structure-Activity Relationship
Substances
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Amidines
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Anti-Inflammatory Agents
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Benzamidines
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Glycosaminoglycans
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Interleukin-1beta
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Protective Agents
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Reactive Oxygen Species
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Nitric Oxide
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Cyclooxygenase 2
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Matrix Metalloproteinase 3