Optimization of 2,3-Dihydroquinazolinone-3-carboxamides as Antimalarials Targeting PfATP4

Ashton, TD; CHURCHYARD, A; Dans, MG; Favuzza, P; Ngo, A; Lehane, AM; Zhang, X; Qiu, D; Chandra Maity, B; De, N; Schindler, KA; Yeo, T; Park, H; Uhlemann, AC; Baum, J; Fidock, DA; Jarman, KE; Lowes, KN; Baud, D; Brand, S; Jackson, PF; Cowman, AF; Sleebs, BE

Author(s): Ashton, TD; CHURCHYARD, A; Dans, MG; Favuzza, P; Ngo, A; Lehane, AM; Zhang, X; Qiu, D; Chandra Maity, B; De, N; Schindler, KA; Yeo, T; Park, H; Uhlemann, AC; Baum, J; Fidock, DA; Jarman, KE; Lowes, KN; Baud, D; Brand, S; Jackson, PF; Cowman, AF; Sleebs, BE;
Details: Publication Year 2023-02-22,Volume 66,Issue #5,Page 3540-3565
Journal Title: Journal of Medicinal Chemistry
Abstract: There is an urgent need to populate the antimalarial clinical portfolio with new candidates because of resistance against frontline antimalarials. To discover new antimalarial chemotypes, we performed a high-throughput screen of the Janssen Jumpstarter library against the Plasmodium falciparum asexual blood-stage parasite and identified the 2,3-dihydroquinazolinone-3-carboxamide scaffold. We defined the SAR and found that 8-substitution on the tricyclic ring system and 3-substitution of the exocyclic arene produced analogues with potent activity against asexual parasites equivalent to clinically used antimalarials. Resistance selection and profiling against drug-resistant parasite strains revealed that this antimalarial chemotype targets PfATP4. Dihydroquinazolinone analogues were shown to disrupt parasite Na(+) homeostasis and affect parasite pH, exhibited a fast-to-moderate rate of asexual kill, and blocked gametogenesis, consistent with the phenotype of clinically used PfATP4 inhibitors. Finally, we observed that optimized frontrunner analogue WJM-921 demonstrates oral efficacy in a mouse model of malaria.
Publisher: ACS
Keywords: Animals; Mice; *Antimalarials/pharmacology/therapeutic use; Plasmodium falciparum; *Malaria; Homeostasis; *Malaria, Falciparum/drug therapy/parasitology
Research Division(s): Chemical Biology; Advanced Technology And Biology; Infectious Diseases And Immune Defence; Infectious Diseases and Immune Defence; Advanced Technology and Biology
PubMed ID: 36812492
Publisher's Version: https://doi.org/10.1021/acs.jmedchem.2c02092
Open Access at Publisher's Site: https://doi.org/10.1021/acs.jmedchem.2c02092
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-03-08 03:15:53

Last Modified: 2023-06-13 01:17:46