2-Amino-1,3-thiazoles Suppressed Lipopolysaccharide-Induced IL-β and TNF-α (2013)

Heterocycles are significant chemical entities for research on small molecule drugs and their development in the pharmaceutical industry. Among the broad range of templates available, heterocyclic scaffolds represent the most promising molecules as leading structures for the discovery of novel synthetic drugs. Thiazole derivatives are highly interesting molecules for drug development, as their usefulness has already been demonstrated for treating various diseases including neurodegenerative disorders. 1 The benzothiazole derivative AS601245 has shown beneficial effects in models of global and focal brain ischemia. 2 Benzothiazoles were identified as huntingtin aggregation inhibitors in high-throughput in vitro screening and subsequently PGL135 (2-amino-4,7-dimethylbenzothiazole) and riluzole (2amino-6-trifluoromethoxy benzothiazole) were shown to inhibit huntingtin aggregation in cell culture. 1(a) Riluzole has been tested for therapy of Huntington's disease patients, where treatment with benzothiazole has positive effects on choreatic hyperkinesia. 3 Various thiazole derivatives have also been reported as drugs to suppress the immune system and as inhibitors of p38 MAP kinase. 4 However, their action mechanisms have not been completely elucidated yet. In addition, structurally distinct classes will be necessary for strengthening our therapeutic concept. We have screened new drugs with a view to developing effective drugs against neuroinflammation-mediated degeneration of neuronal cells. We previously reported that 2-cyclopropylimino-3-methyl1,3-thiazoline hydrochloride suppressed glutamate-induced excitotoxicity in rat glial cultures 5 and inhibited glutamate dehydrogenase activity in cultured islets. 6 As an extension of our efforts to investigate the biological activities of the analogues, we report here that 2-aminothiazole derivatives effectively suppress the lipopolysaccharide (LPS)-induced interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) level. Cytokines, as major effectors of the inflammatory cascade, have key roles in the nerve cell response to brain injury. 7 Elevated levels of cytokines have been associated with the pathological effects of a variety of infectious, neurological, neurodegenerative, and neurotoxic conditions. LPS injected into the rat hippocampus CA1 region activated microglial cells, leading to an increased production of IL-1β and TNFα in the hippocampus. 8 IL-1 ligands (IL-1α and IL-1β, collectively referred to as IL-1) are pluripotent, proinflammatory cytokines that orchestrate inflammatory and host defense responses in the body. 9 IL-1 augments T-cell responses to mitogens (and indirectly activates B cells), increases expression of vascular adhesion molecules, and induces a number of other proinflammatory cytokines, chemokines, and inflammation-associated molecules that form an amplifying cascade to stimulate an immune response. 9 IL-1β has been reported to show toxicity to oligodendrocytes, and can exacerbate inflammation of the brain. 10 The cytokine possesses both growth-stimulating and -inhibitory properties, and it appears to have self regulatory properties as well. For instance, TNF-α induces neutrophil proliferation during inflammation, but it also induces neutrophil apoptosis upon binding to the TNF-R55 receptor. 11 The pathological activities of TNF-α have attracted much attention. For instance, although TNF-α causes necrosis of some types of tumors, it promotes the growth of other types of tumor cells. High levels of TNF-α are correlated with increased risk of mortality. 12