Structure-Guided Optimization of Novel Inhibitors of Plasmodium Lysyl-tRNA Synthetase with Multistage Activity against Malaria Parasites

  • J Med Chem. 2026 Jun 11;69(11):13820-13855. doi: 10.1021/acs.jmedchem.6c00823.
Barbara Forte  1 ,  Fiona Bellany  1 ,  Peter S Campbell  1 ,  Giulia Chemi  1 ,  Alice Dawson  1 ,  Mark Anderson  1 ,  Yaw Aniweh  2 ,  Anna Y Burkhard  3  4 ,  Anna Caroline Campos Aguiar  5 ,  Alisje Churchyard  6 ,  Caitlin A Cooper  7 ,  Amália Dos Santos Ferreira  8 ,  Mufuliat Toyin Famodimu  6  9 ,  Francis G Fang  10 ,  Xiao Hu  1 ,  Tonnie Huijs  11 ,  Delphine Baud  12 ,  Chimed Jansen  1 ,  María Belén Jiménez Díaz  13 ,  Roger Bonnert  12 ,  Susan Boyd  12 ,  Benigno Crespo-Fernández  14 ,  Branko Mitasev  10 ,  Simone Montagna  1 ,  Sachel Mok  3  4  15 ,  Dinakaran Murugesan  1 ,  Sunil K Narwal  3  4 ,  Neil R Norcross  1 ,  John Okombo  3  4 ,  Heekuk Park  4  15 ,  Caroline Peet  1 ,  Dhelio B Pereira  16 ,  John M Post  1 ,  Janette Reader  17 ,  Jennifer Riley  1 ,  David A Robinson  1 ,  Raku Shinkyo  10 ,  Frederick R C Simeons  1 ,  Laura Simpson  1 ,  Alasdair Smith  1 ,  Dennis Smith  12 ,  Josefine Striepen  3  4 ,  Carolina B G Teles  8 ,  Rianne van der Laak  11 ,  Anne-Catrin Uhlemann  4  15 ,  Amélie Vantaux  18 ,  Caroline Wilson  1 ,  Benoît Witkowski  19 ,  Gavin Wood  1 ,  Tomas Yeo  3  4 ,  Fabio Zuccotto  1 ,  Iñigo Angulo-Barturen  13 ,  Jake Baum  6 ,  Judith M Bolscher  11 ,  Rafael Victorio Carvalho Guido  19 ,  Lyn-Marié Birkholtz  20 ,  Michael J Delves  6  9 ,  Laurent Dembele  21 ,  David A Fidock  3  4  15 ,  Francisco Javier Gamo  14 ,  Dennis E Kyle  7 ,  Steven P Maher  7 ,  Jean Popovici  22  23 ,  Chris Walpole  24 ,  Fabian Gusovsky  10 ,  Paul A Willis  12 ,  Kevin D Read  1 ,  Ian H Gilbert  1 ,  Beatriz Baragaña  1
Affiliations
  • 1. Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
  • 2. West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), College of Basic and Applied Sciences, University of Ghana, Accra LG54, Ghana.
  • 3. Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, New York 10032, United States.
  • 4. 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.
  • 5. Department of Microbiology, Immunology, and Parasitology, Federal University of São Paulo, São Paulo, São Paulo CEP 04023-062, Brazil.
  • 6. Department of Life Sciences, Imperial College, London SW7 2AZ, U.K.
  • 7. Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia 30602-0002, United States.
  • 8. Oswaldo Cruz Foundation, Leishmaniasis and Malaria Bioassay Platform, Porto Velho, Rondônia CEP 76812-245, Brazil.
  • 9. Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, U.K.
  • 10. Eisai, Inc., 35 Cambridge Park Drive Suite 200, Cambridge, Massachusetts 02140, United States.
  • 11. TropIQ Health Sciences, Nijmegen 6534 AT, The Netherlands.
  • 12. MMV Medicines for Malaria Venture, ICC, Geneva 1215, Switzerland.
  • 13. The Art of Discovery, Derio 48160, Spain.
  • 14. Global Health Medicines R&D, GSK, Tres Cantos, Madrid 28760, Spain.
  • 15. Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York 10032, United States.
  • 16. Research Center in Tropical Medicine of Rondônia, Porto Velho, Rondônia CEP 76812-329, Brazil.
  • 17. Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control University of Pretoria, Hatfield, Pretoria 0028, South Africa.
  • 18. Malaria Molecular Epidemiology Unit, Institut Pasteur du Cambodge, Phnom Penh 120210, Cambodia.
  • 19. São Carlos Institute of Physics, University of São Paulo, São Carlos, São Paulo CEP 13563-120, Brazil.
  • 20. Department of Biochemistry, Stellenbosch University, Stellenbosch, Matieland 7602, South Africa.
  • 21. Univerité Des Sciences, Des Techniques Et Des Technologies de Bamako (USTTB), Parasite and Microbe Research and Training Centre (P-MRTC), Faculty of Pharmacy, Point G, Bamako BP 1805, Mali.
  • 22. Malaria Research Unit, Institut Pasteur du Cambodge, Phnom Penh 120210, Cambodia.
  • 23. Infectious Disease Epidemiology and Analytics G5 Unit, Institut Pasteur, Université Paris Cité, Paris 75015, France.
  • 24. Structural Genomics Consortium, Research Institute of the McGill University Health Centre, Montreal, Québec H4A 3J1, Canada.
PMID: 42227818 DOI: 10.1021/acs.jmedchem.6c00823
Abstract

A fused dihydropyrrolidino-pyrimidine hit with low lipophilicity and excellent ligand efficiency was identified in a biochemical screen of the Global Health Chemical Diversity Library (GHCDL) against Plasmodium lysyl-tRNA synthetase (KRS). Structure-guided lead optimization delivered analogues with potent Parasite growth inhibition, excellent biochemical and cellular selectivity (>1000-fold), and oral efficacy in the malaria NOD-scid-IL2Rγnull (SCID) mouse model. Structural information and computational methods were deployed to identify a potent and selective basic KRS inhibitor (30) with an extended half-life to reduce the dose regimen to a single-dose cure. Compound 30 displayed a long half-life across preclinical species, favorable safety, and activity across Plasmodium species as well as against drug-resistant and sensitive P. falciparum strains and field isolates. Unfortunately, 30 lacked oral bioavailability, which could not be mitigated with a prodrug approach. Nevertheless, learnings from this series will assist future KRS programs in delivering a clinical candidate with this novel mode of action.

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