Synthesis of Clovamide Analogues That Inhibit NO Production in Activated BV-2 Microglial Cells

A series of methyl ester of clovamide analogues, where the hydroxyl group of catechol moiety in caffeic acid and L-3,4-dihydroxyphenylalanine (L-dopa) was replaced with various functional groups, were synthesized and their inhibitory effects on nitric oxide (NO) production and inducible NO synthase (iNOS) expression in lipopolysaccharide (LPS)-induced BV2 cells were tested. Among the synthesized compounds, 3,5-ditrifluoromethyl analogue 91 (IC50=2.84 mu M) exhibited a potency about 26.3 times greater than that of the parent compound 9a (IC50=73.6 mu M) and suppressed NO production dose-dependently without cytotoxicity. Compound 91 also inhibited iNOS expression in LPS-induced BV2 cells at 2.5, 5 and 10 mu M concentrations. These results suggested that the dihydroxyl group of catechol moiety in caffeic acid unit is not essential for the suppression of NO production and that 91 has potential as a potent inhibitor of NO production.