Synthesis and Anti-inflammatory Evaluation of Novel 1,2,3-Triazole Derivatives

As the role of indoleamine 2,3-dioxygenase 2 (IDO2) in inflammation, especially in rheumatoid arthritis (RA), is gradually being explained, IDO2 has become a potential target for the treatment of RA. No small molecule inhibitor of IDO2 with strong activity and high selectivity has been reported yet. With the help of computer-aided drug design, twenty-four 1,2,3-triazole derivatives were designed and synthesized by using epacadostat as a lead compound. The results of biological activity show that all target compounds display the inhibitory effects on IDO1 and IDO2 enzymes. Among them, the inhibition rates of (Z)-N-((1-(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxyformamidine)-1,2,5-oxadiazo-3-yl)amino)ethyl)-1H-1,2,3triazol-4-yl)methyl) (I-11) on indoleamine 2,3-dioxygenase 1 (IDO1) and IDO2 enzymes were 76% and 49% at 100 nmol/L concentration, respectively, which are better than those of epacadostat (62% and 25%). The anti-inflammatory activity study showed that compound I-11 could significantly inhibit the secretion of inflammatory factor TNF-a at the cellular level. Compound I-11 also showed good in vivo anti-inflammatory activity in mouse ear swelling model, and the inhibition rate was 56.81% at the dose of 100 mg/kg (Ig) which was better than that of naproxen (45.29%, 150 mg/kg, Ig).