2025/07/01 by Joyshree Karmakar, S. C. Pal, Maximilian Johannes Braun +3 · 1 voice
Chemistry · Medicine · #Research on Leishmaniasis Studies #Synthesis and Biological Evaluation #Synthesis and Characterization of Heterocyclic Compounds
paper · pdf · doi:10.1093/narmme/ugaf027
openalex publication_date 2025/07/01 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
Abstract Visceral leishmaniasis (VL), caused by Leishmania donovani (L.d), is a severe, immunosuppressive disease with global impact, with limited treatment options, highlighting the need for more effective therapies. In this study, we report the antileishmanial and immunomodulatory potential of IQ2, a pyrrolidine substituted triazolyl 6H-indolo[2,3-b]quinoxaline derivative, synthesized via copper-assisted azide-alkyne cycloaddition. IQ2 exhibits potent activity against both promastigote and amastigote forms at low micromolar concentrations, with minimal toxicity to host macrophages. Mechanistically, IQ2 selectively stabilized the c-MYC G-quadruplex (G4) and suppressed c-MYC transcription and translation; shifting the macrophage polarization from the disease-promoting M2 phenotype to the host-protective M1 phenotype. This enhanced the proinflammatory cytokine production and nitric oxide levels, crucial for parasite clearance. Furthermore, IQ2 activated the Toll-like receptor 4 (TLR4)-mediated MAPK signaling pathway, amplifying the host immune response. These results highlight IQ2 as a promising host-directed therapeutic agent against VL through immune restoration and parasite eradication.