Synthesis of Heterocycle-linked Thioureas and Their Inhibitory Activities of NO Production in LPS Activated Macrophages

A series of thioureas were synthesized as inhibitors of NO production in lipopolysaccharide-activated macrophages. We investigated the effect of lipophilic moiety and N-substituents of the thioureas on the activity. Phenoxazine and carbazole-containing derivatives revealed higher activity than indole-containing thioureas. The appropriate spacer between lipophilic tail and thiourea head and methyl substituent at N3 position of thiourea brought beneficial effect on the inhibition of NO production. Among prepared compounds, phenoxazine-containing derivative 2a was the most potent with $2.32 {\mu}M$ of $IC_{50}$ value. RT-PCR analysis suggested that the prepared thioureas inhibited NO production through the suppression of iNOS mRNA expression.