Trisubstituted Pyrimidines as Efficacious and Fast-Acting Antimalarials

Area of Science:

• Medicinal Chemistry
• Parasitology
• Pharmacology

Background:

• Malaria remains a significant global health challenge, necessitating the development of new antimalarial drugs.
• Trisubstituted pyrimidine scaffolds have shown potential as a basis for antimalarial drug discovery.

Purpose of the Study:

• To optimize a phenotypic hit compound based on a trisubstituted pyrimidine scaffold for antimalarial activity.
• To evaluate the pharmacokinetic properties and in vivo efficacy of optimized compounds against Plasmodium falciparum.

Main Methods:

• Phenotypic screening and structure-activity relationship (SAR) studies were employed to optimize the lead compound.
• In vivo antimalarial activity was assessed using Plasmodium berghei and Plasmodium falciparum mouse models.
• Pharmacokinetic profiling and cytochrome P450 inhibition assays were performed.

Main Results:

• Optimization yielded compounds with good pharmacokinetics and oral antimalarial activity.
• Compound 13 demonstrated a 96% reduction in parasitemia in the P. berghei model at 30 mg/kg/day.
• Compound 13 showed rapid clearance of erythrocytic stages in SCID mice with an ED90 of 11.7 mg/kg but potently inhibited cytochrome P450 enzymes.

Conclusions:

• The optimized trisubstituted pyrimidine compound 13 exhibits a promising antimalarial profile with significant in vivo efficacy.
• Cytochrome P450 inhibition by compound 13, likely due to the 4-pyridyl group, presents a challenge for further development.
• This lead molecule warrants further optimization or can be utilized for target identification in malaria research.