8-Fluorotryptanthrin, an immunomodulatory IDO-1 inhibitor enhances the efficacy of artemether-lumefantrine in the treatment of malaria.

Malaria remains a major global health threat, exacerbated by increasing drug resistance and limited immunological protection. This study investigates the anti-plasmodial and immunomodulatory efficacy of novel synthetic heterocyclic compounds targeting indoleamine 2,3-dioxygenase-1 (IDO-1), a key regulator of immune suppression during malaria. Among the tested compounds, 8-fluorotryptanthrin (C1), exhibited the most promising profile with strong in vitro activity against Plasmodium falciparum (3D7 and Dd2 strains) and P. berghei ANKA with high selectivity indices and minimal cytotoxicity and haemolysis. The in vivo studies in P. berghei-infected BALB/c mice demonstrated that C1, particularly at 20 mg/kg body weight, significantly reduced parasitaemia, restored liver and kidney functions, enhanced survival, and modulated T-cell and B-cell populations. Most importantly, combination therapy of this IDO-1 inhibitor (C1) with artemether-lumefantrine led to best immunochemotherapeutic effects, with complete parasitaemia suppression and full survival along with enhanced immune restoration by D7 and D14. Elevated levels of nitric oxide and reactive oxygen species, along with balanced cytokine profiles (increased IL-10 and IL-4 along with reduced TNF-α and IFN-γ levels on D14 post-infection), further confirmed the immunotherapeutic potential of C1. These findings support C1 as a promising lead candidate for immunochemotherapy against drug-resistant malaria.