2-Amino-3,4-Dihydroquinazolines Exhibit Potent Antimalarial Activity by Targeting Plasmepsin X

The emergence of resistance to most clinically used antimalarials necessitates the discovery of new chemotypes. A phenotypic screen against asexual Plasmodium falciparum identified the 2-amino-3,4-dihydroquinazoline scaffold, previously developed as a β-secretase 1 inhibitor for Alzheimer's disease. Evaluation of hit analogues against malarial aspartyl proteases revealed potent inhibition of plasmepsin X. Structure-activity analysis showed that key motifs on the hit scaffold are required for driving biochemical and antimalarial but are associated with poor selectivity against human aspartyl proteases and low metabolic stability. Plasmepsin X was validated as the molecular target through forward genetics, activity against mutant parasites, and inhibition of plasmepsin X substrate processing. 2-Amino-3,4-dihydroquinazoline analogs exhibit moderate asexual killing rates, low-to-moderate resistance risk, no cross-resistance with multidrug-resistant strains, and transmission-blocking activity. Further optimization of potency and metabolic stability will be required to achieve in vivo efficacy and realize the potential of this antimalarial class.