Quinoxaline-based anti-schistosomal compounds have potent anti-plasmodial activity

Area of Science:

• Drug discovery and development
• Parasitology
• Medicinal chemistry

Background:

• Plasmodium (malaria) and Schistosoma (schistosomiasis) cause millions of infections globally.
• Drug resistance in Plasmodium and limited targets for Schistosoma necessitate new therapeutics.
• Pathogen-hopping offers a strategy to repurpose anti-schistosomal compounds for malaria.

Purpose of the Study:

• To evaluate quinoxaline-based anti-schistosomal compounds for activity against Plasmodium falciparum.
• To identify potential drug targets and understand resistance mechanisms in P. falciparum.

Main Methods:

• Screening of quinoxaline compounds against P. falciparum strains (3D7 and multidrug-resistant).
• In vitro resistance selection experiments using wildtype and mutator P. falciparum.
• Genetic analysis including CRISPR-editing and copy number variation studies.
• Biochemical assays to investigate enzyme activity and resistance mechanisms.

Main Results:

• Identified quinoxaline compounds with low nanomolar potency against P. falciparum.
• Observed a low propensity for resistance development, with resistance linked to mutations in pfqrp1 and amplification of pfatp2.
• Demonstrated that pfqrp1 mutations and pfatp2 copy number variations confer resistance.
• Confirmed that predicted hydrolase activity of PfQRP1 is involved in the resistance mechanism.

Conclusions:

• Quinoxaline derivatives are potent against P. falciparum, suggesting a viable 'pathogen-hopping' strategy.
• PfQRP1 and PfATP2 are identified as potential targets or mediators of resistance.
• This research provides a promising new class of compounds for treating malaria.