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

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

  • J Med Chem. 2023 Mar 9;66(5):3540-3565. doi: 10.1021/acs.jmedchem.2c02092.
Trent D Ashton 1 2,  Madeline G Dans 1 2,  Paola Favuzza 1 2,  Anna Ngo 1 2,  Adele M Lehane 3,  Xinxin Zhang 3,  Deyun Qiu 3,  Bikash Chandra Maity 4,  Nirupam De 4,  Kyra A Schindler 5,  Tomas Yeo 5,  Heekuk Park 5,  Anne-Catrin Uhlemann 5,  Alisje Churchyard 6,  Jake Baum 6 7,  David A Fidock 5 8,  Kate E Jarman 1 2,  Kym N Lowes 1 2,  Delphine Baud 9,  Stephen Brand 9,  Paul F Jackson 10,  Alan F Cowman 1 2,  Brad E Sleebs 1 2
Affiliations

Affiliations

  • 1 The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.
  • 2 Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
  • 3 Research School of Biology, Australian National University, Canberra 2601, Australia.
  • 4 TCG Lifesciences Pvt. Ltd., Saltlake Sec-V, Kolkata 700091, West Bengal, India.
  • 5 Department of Microbiology & Immunology, Columbia University, Irving Medical Center, New York, New York 10032, United States.
  • 6 Department of Life Sciences, Imperial College London, South Kensington SW7 2AZ U.K.
  • 7 School of Biomedical Sciences, University of New South Wales, Sydney 2031, Australia.
  • 8 Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University, Irving Medical Center, New York, New York 10032, United States.
  • 9 Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, 1215 Geneva, Switzerland.
  • 10 Global Public Health, Janssen R&D LLC, La Jolla, California 92121, United States.
PMID: 36812492 DOI: 10.1021/acs.jmedchem.2c02092
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.

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