Phenotypic screening reveals a highly selective phthalimide-based compound with antileishmanial activity

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Discovery

Background:

• Phthalimide (PHT) and hydroxyethylamine (HEA) pharmacophores are explored for anti-parasitic drug development.
• Existing treatments for leishmaniasis require new, cost-effective, and efficient alternatives.
• Effective antileishmanials must penetrate host cells to eliminate intracellular parasites.

Purpose of the Study:

• To identify novel anti-parasitic compounds through phenotypic screening of PHT and HEA derivatives.
• To evaluate the efficacy of identified compounds against Leishmania infantum intracellular amastigotes.
• To elucidate the mode of action and cellular entry pathway of promising drug candidates.

Main Methods:

• Phenotypic screening of PHT and HEA derivatives against protist parasites, including Entamoeba histolytica, Trypanosoma brucei, and Leishmania spp.
• Intramacrophage assay to assess the efficacy of compounds against L. infantum intracellular amastigotes.
• Cytotoxicity testing in HepG2 cells and chemogenomic profiling using a T. brucei RNA interference library.

Main Results:

• Several compounds showed significant activity against E. histolytica, T. brucei, and Leishmania spp.
• PHT-39 exhibited potent efficacy against L. infantum intracellular amastigotes (EC50 = 1.2 ± 3.2 μM) with high selectivity (>90-fold).
• Chemogenomic profiling indicated PHT-39 utilizes a P-type ATPase for cellular entry, shared with miltefosine and amphotericin.

Conclusions:

• PHT-39 is a highly promising antileishmanial candidate with a favorable selectivity profile and a defined cellular uptake mechanism.
• Further derivatization of PHT-39 is underway to optimize its pharmacological properties for potential therapeutic application.
• The study highlights the potential of PHT and HEA scaffolds in developing new anti-parasitic agents.