Syntheses of Ethyl Pyruvate's Bioisosteres Inhibiting Inducible Nitric Oxide Production in Lipopolysaccharide-induced BV2 Cells

Various bioisosteres of ethyl pyruvate (EP), where the oxygen atom in the ethoxy group was replaced by the corresponding bioisosteric atom such as carbon, nitrogen, and sulfur atoms, were synthesized and their inhibitory effects were tested for nitric oxide (NO) production and inducible NO synthase (iNOS) expression in lipopolysaccharide (LPS)-induced BV2 cells. The synthesized compounds generally revealed better activity than EP. Especially, the thio-bioisostere 4c (IC50 = 3.6 mu M) exhibited a potency about 4.5 times greater than that of EP (IC50 = 16.1 mu M) and suppressed NO production dose-dependently without cytotoxicity. Compound 4c also inhibited iNOS expression in LPS-induced BV2 cells at 1 mu M and 10 mu M concentrations. These results suggested that the ethoxy group in EP is not essential for the suppression of NO production and that 4c has potential as a potent inhibitor of NO production.