Efficient and Rapid Arylation of NH₂‐Unprotected Bromobisindole Ethanamines via Suzuki‐Miyaura Coupling: Generating New Leads Against Leishmania

Leishmaniasis is a neglected tropical disease which presents significant global health challenges due to the lack of effective vaccines and the limitations of existing chemotherapeutics in view of their toxicity, resistance, and high costs. In this study, we realized a library of novel bisindole derivatives as potential antileishmanial agents through a rapid Suzuki-Miyaura coupling reaction, utilizing NH2-unprotected bromobisindole ethanamines and boronic acids. Optimization of reaction conditions allowed for the efficient and selective arylation of these substrates, with yields up to 93%. The compounds were screened for their activity against Leishmania infantum promastigotes. Among the tested bisindole derivatives, 3af (bearing a 4-vinylphenyl moiety) demonstrated potent antileishmanial activity (IC50 = 1.1 µM) with a higher selectivity index (21.8) compared to the reference drug miltefosine (9.8). A significant activity was also retained against intracellular amastigotes. This study establishes a robust methodology for late-stage functionalization of bisindoles, also highlighting these derivatives' potential as promising leads for antileishmanial drug development.