Indolylmaleimide derivatives as a new class of anti-leishmanial agents: synthesis and biological evaluation

Abstract

Leishmaniasis is a neglected tropical disease, primarily affecting poor and developing countries. The present therapeutic approach faces various limitations, such as concerns regarding toxicity, route of administration, and the emergence of drug resistance. Therefore, there is a critical need to identify novel scaffolds to combat this fatal parasitic infection. Leishmanial DNA topoisomerase 1B is a heterodimeric protein and plays a crucial role in resolving topological problems during various biological processes. It is structurally distinct from its human counterparts, making it an attractive target for drug discovery. In this study, we synthesized various aminated indolylmaleimide derivatives targeting the leishmanial topoisomerase 1B enzyme. In vitro leishmanicidal assays on Leishmania promastigotes identified one highly potent hit (3m), showing considerable inhibition with single-digit micromolar IC₅₀ values. Moreover, molecular docking analysis of the potent hit (3m) confirmed its strong binding affinity with the enzyme. Thus, the hit molecule (3m) holds promise as a lead for developing novel therapeutic strategies against leishmaniasis.