Development of Imiqualine compounds with enhanced activity against cutaneous leishmaniasis.

Cutaneous leishmaniasis (CL) is a neglected tropical disease still inflicting a high number of individuals worldwide with a rising prevalence in the Eastern Mediterranean region. Current treatment options remain hindered by substantial toxicity, high relapse rates, and emergence of drug resistance. Imiqualines, a family of heterocyclic aromatic compounds, garnered increasing interest for their broad antiparasitic activity, particularly against CL. The parent immunomodulatory compound Imiquimod has been used in clinical trials for the treatment of relapsed cases of CL, yet its clinical use was constrained by significant adverse effects. This study evaluated the efficacy of a panel of forty-eight Imiqualine compounds, against Leishmania tropica, a major causative agent of CL. Among these, the imidazo[1,2-a]quinoxaline EAPB04003 and the [1,2,4]triazolo[4,3-a]quinoxaline EAPB4003 demonstrated strong leishmanicidal effects, markedly reducing the percentage of infected macrophages and intracellular amastigote burden in a dose and time-dependent manner. Transcriptomic profiling revealed that both compounds modulate the host immune response by restoring altered expression of key inflammatory and immune-related genes, and by effectively counteracting molecular signatures associated with CL lesions. These findings support their potential as promising immunomodulatory candidates for more effective and better tolerated therapies against L. tropica infections.