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

Dans, MG; Awalt, JK; Nguyen, N; Palandri, J; Ngo, A; Jarman, KE; Jeon, JH; Yeo, T; Park, H; Uhlemann, AC; Mao, EY; Gancheva, MR; Wilson, DW; Mukherjee, P; Chakraborty, A; Kristan, M; Stewart, L; Sutherland, CJ; Baud, D; Brand, S; Fidock, DA; Jackson, PF; Cowman, AF; Sleebs, BE

Author(s): Dans, MG; Awalt, JK; Nguyen, N; Palandri, J; Ngo, A; Jarman, KE; Jeon, JH; Yeo, T; Park, H; Uhlemann, AC; Mao, EY; Gancheva, MR; Wilson, DW; Mukherjee, P; Chakraborty, A; Kristan, M; Stewart, L; Sutherland, CJ; Baud, D; Brand, S; Fidock, DA; Jackson, PF; Cowman, AF; Sleebs, BE;
Details: Publication Year 2026-08-14,Volume 12,Issue #8,Page 2713-2726
Journal Title: ACS Infectious Diseases
Abstract: 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 beta-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.
Publisher: ACS
Keywords: *Antimalarials/pharmacology/chemistry; *Plasmodium falciparum/drug effects/enzymology/genetics; *Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism/genetics; *Quinazolines/pharmacology/chemistry; Humans; Structure-Activity Relationship; Animals; *Protozoan Proteins/antagonists & inhibitors/genetics/metabolism; Drug Resistance; Malaria, Falciparum/parasitology/drug therapy; Plasmodium; antimalarial; malaria; plasmepsin; beta-secretase
Research Division(s): New Medicines and Diagnostics; Structural Biology
PubMed ID: 42424440
Publisher's Version: https://doi.org/10.1021/acsinfecdis.6c00258
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-07-15 09:14:53

Last Modified: 2026-08-28 10:57:40