Rational design of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors featuring 1,2,3-triazole derivatives with enhanced anti-inflammatory and analgesic efficacy.

Abstract

This study applied a target-based drug design approach focused on the IDO1 enzyme, which features a heme active site. By introducing a 1,2,3-triazole moiety capable of coordinating with the ferrous ion in heme, a series of 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives were designed. Enzyme assays demonstrated that these compounds generally inhibited IDO1 activity, with Compound 14e showing the most potent effect, achieving an IC₅₀ value of 3.63 μM. Molecular docking studies indicated that the 1,2,3-triazole ring in Compound 14e is positioned directly above the heme, forming a coordination bond with the ferrous ion. Additionally, it engages in π-π interactions with Phe263, while the amide group of the 2H-benzo[b][1,4]oxazin-3(4H)-one scaffold forms hydrogen bonds with Lys238. In vivo experiments in mice showed that Compound 14e significantly reduced CFA-induced upregulation of Iba1 in the spinal dorsal horn and alleviated mechanical hypersensitivity, thermal hyperalgesia, and spontaneous pain. Moreover, treatment with Compound 14e led to a significant reduction in the levels of pro-inflammatory cytokines TNF-α and IL-1β in CFA-treated mice. Importantly, Compound 14e demonstrated a favorable safety profile, with no observed toxicity in major organs, highlighting its potential as a promising anti-inflammatory and analgesic agent targeting IDO1.