High-throughput phenotypic screening identifies novel antimalarial scaffolds and target-associated chemotypes

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Discovery

Background:

• Artemisinin resistance in Plasmodium falciparum malaria poses a significant threat to global health.
• Novel antimalarial agents with new mechanisms of action are urgently required to combat drug-resistant malaria strains.

Purpose of the Study:

• To identify novel antimalarial compounds with new mechanisms of action through high-throughput phenotypic screening.
• To discover new chemical scaffolds targeting validated Plasmodium falciparum drug targets.

Main Methods:

• High-throughput phenotypic screening of the Nagoya Chemical Library (36,160 compounds).
• Differential screening to identify inhibitors of mitochondrial electron transport chain, including dihydroorotate dehydrogenase (DHODH).
• Profiling against a multidrug-resistant Plasmodium falciparum panel and chemical clustering to identify novel scaffolds.

Main Results:

• 1391 primary hits were identified, with a subset of 441 potent compounds selected based on cytotoxicity and EC50 values.
• Compounds targeting Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH), phosphatidylinositol 4-kinase (PfPI4K), and P-type ATPase 4 (PfATP4) were identified.
• Novel chemical scaffolds with antiplasmodial activity, structurally distinct from known antimalarials, were discovered.

Conclusions:

• The study identified novel chemotypes targeting validated antiplasmodial targets (PfDHODH, PfPI4K, PfATP4).
• Previously uncharacterized scaffolds with potential antimalarial activity and unknown targets were uncovered.
• These compounds represent a valuable foundation for developing new antimalarial drugs against resistant Plasmodium falciparum strains.