Optimization and Characterization of N-Acetamide Indoles as Antimalarials That Target PfATP4

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Discovery

Background:

• Malaria remains a significant global health challenge, necessitating the development of new antimalarial drugs.
• The identification of novel drug targets and chemical scaffolds is crucial for overcoming drug resistance.

Purpose of the Study:

• To identify and optimize novel antimalarial compounds targeting Plasmodium falciparum.
• To validate PfATP4 as a drug target for malaria treatment.

Main Methods:

• High-throughput screening of the Janssen Jumpstarter library against Plasmodium falciparum.
• Structure-activity relationship studies and lead optimization.
• Resistant selection, whole-genome sequencing, and target validation assays (metabolomics, ATPase activity).

Main Results:

• Identified N-acetamide indoles as a novel antimalarial hit class.
• Optimized analog WJM664 demonstrated potent asexual stage activity and metabolic stability.
• PfATP4 was validated as the target, with WJM664 showing reduced potency against resistant strains and inhibiting Na+-dependent ATPase activity.
• WJM664 inhibited parasite transmission but showed low efficacy in a Plasmodium berghei mouse model due to species-specific ATP4 differences and exposure.

Conclusions:

• N-acetamide indoles represent a promising chemotype for antimalarial drug development targeting PfATP4.
• Further optimization is needed to improve efficacy in vivo and address species-specific target variations for curative and transmission-blocking therapies.