Add time:07/25/2019         Source:sciencedirect.com

In order to more rationally design thiourea-containing drugs and drug candidates, specifically thiourea-containing histamine H3 receptor antagonists, it is necessary to develop structure–toxicity relationships (STRs). For this purpose, the cytotoxicity of a series of thiourea-containing compounds was tested in precision-cut rat liver slices. A concentration of 1000 μM of N-p-bromophenyl, N′-(4-imidazole-ethyl)thiourea (8) or N-p-nitrophenyl, N′-(4-imidazole-ethyl)thiourea (9) was found to cause cytotoxicity, evidenced as LDH leakage, resulting in more than 95% LDH leakage after 6 h. N-p-Methoxyphenyl, N′-(4-imidazole-ethyl)thiourea (6) caused 40.6±19.7% LDH leakage after 6 h. Control levels of cell death (1% methanol as control vehicle) were below 20% in 6 h. After 6 h of exposure, N-p-chlorophenyl, N′-(4-imidazole-ethyl)thiourea (7), 8, and 9 were already found to cause significant cytotoxicity at a concentration of 100 μM. At 200 μM, 9 was found to cause significantly more cytotoxicity than 7 and 8. N-Naphthyl, N′-(4-imidazole-ethyl)thiourea (12) was found to cause significant cytotoxicity towards precision-cut rat liver slices after 6 h of exposure to a concentration of 500 μM. All other N-substituted, N′-(4-imidazole-ethyl)thiourea tested in this study were not found to be cytotoxic towards precision-cut rat liver slices within the 6 h of exposure up to a concentration of 1000 μM. Intracellular glutathione (GSH) content and mitochondrial MTT reduction activity were also examined after exposure of slices to N-substituted, N′-(4-imidazole-ethyl)thiourea. Both of these markers, however, were not found to provide additional information regarding the possible mechanisms of cytotoxicity, i.e. GSH depletion or reduced mitochondrial activity since these markers did not clearly precede LDH leakage.A correlation was found between cytotoxicity towards precision-cut rat liver slices and Vmax/Km values for the formation of sulfenic acids from N-substituted N′-(4-imidazole-ethyl)thiourea by hepatic rat flavin-containing monooxygenases (FMO). The compound with the highest Vmax/Km value for the formation of sulfenic acids, 9, was also the most cytotoxic. Compounds with a significantly lower Vmax/Km value, 7, 8, and 12, were less cytotoxic than 9. Compounds with a Vmax/Km value for the formation of sulfenic acids lower than 0.0788 ml/(min mg) were found not to be cytotoxic towards precision-cut rat liver slices for concentrations up to 1000 μM at an exposure time of 6 h.It is concluded, from this study, that N-phenyl substituted N′-(4-imidazole-ethyl)thiourea-containing electron-withdrawing p-substituents are cytotoxic towards precision-cut rat liver slices. Cytotoxicity is increased with increasing electron-withdrawing capacity of the p-substituent. A correlation was found to exist between Vmax/Km value for the formation of sulfenic acids by rat liver FMO enzymes and cytotoxicity.

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