2. Academic Validation
  3. Optimization of pyrazolopyridine 4-carboxamides with potent antimalarial activity for which resistance is associated with the P. falciparum transporter ABCI3

Optimization of pyrazolopyridine 4-carboxamides with potent antimalarial activity for which resistance is associated with the P. falciparum transporter ABCI3

  • Eur J Med Chem. 2024 Jul 14:276:116677. doi: 10.1016/j.ejmech.2024.116677.
Petar P S Calic 1,  Trent D Ashton 1,  Mahta Mansouri 1,  Katie Loi 1,  Kate E Jarman 1,  Deyun Qiu 2,  Adele M Lehane 2,  Sayantan Roy 3,  Gunturu P Rao 3,  Bikash Maity 3,  Sergio Wittlin 4,  Benigno Crespo 5,  Franciso-Javier Gamo 5,  Ioanna Deni 6,  David A Fidock 6,  Mrittika Chowdury 7,  Tania F de Koning-Ward 7,  Alan F Cowman 1,  Paul F Jackson 8,  Delphine Baud 9,  Stephen Brand 9,  Benoît Laleu 9,  Brad E Sleebs 10
Affiliations

Affiliations

  • 1 The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
  • 2 Research School of Biology, Australian National University, Canberra, 2601, Australia.
  • 3 TCG Lifesciences, Kolkata, West Bengal, 700091, India.
  • 4 Swiss Tropical and Public Health Institute, Kreuzstrasse 2, 4123, Allschwil, Switzerland; University of Basel, 4003, Basel, Switzerland.
  • 5 Global Health Medicines R&D, GSK, Tres Cantos, 28760, Spain.
  • 6 Department of Microbiology & Immunology, Columbia University, Irving Medical Center, New York, 10032, NY, USA; Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University, Irving Medical Center, New York, 10032, NY, USA.
  • 7 School of Medicine, Deakin University, Waurn Ponds, Victoria, 3216, Australia; Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, Victoria, 3216, Australia.
  • 8 Global Public Health, Janssen R&D LLC, La Jolla, 92121, USA.
  • 9 MMV Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, 1215, Geneva, Switzerland.
  • 10 The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia. Electronic address: sleebs@wehi.edu.au.
PMID: 39024967 DOI: 10.1016/j.ejmech.2024.116677
Abstract

Emerging resistance to current antimalarials is reducing their effectiveness and therefore there is a need to develop new antimalarial therapies. Toward this goal, high throughput screens against the P. falciparum asexual Parasite identified the pyrazolopyridine 4-carboxamide scaffold. Structure-activity relationship analysis of this chemotype defined that the N1-tert-butyl group and aliphatic foliage in the 3- and 6-positions were necessary for activity, while the inclusion of a 7'-aza-benzomorpholine on the 4-carboxamide motif resulted in potent Anti-parasitic activity and increased aqueous solubility. A previous report that resistance to the pyrazolopyridine class is associated with the ABCI3 transporter was confirmed, with pyrazolopyridine 4-carboxamides showing an increase in potency against parasites when the ABCI3 transporter was knocked down. The low metabolic stability intrinsic to the pyrazolopyridine scaffold and the slow rate by which the compounds kill asexual parasites resulted in poor performance in a P. berghei asexual blood stage mouse model. Lowering the risk of resistance and mitigating the metabolic stability and Cytochrome P450 inhibition will be challenges in the future development of the pyrazolopyrimidine antimalarial class.

Keywords

ABCI3 transporter; Antimalarial; Malaria; Plasmodium; Pyrazolopyridine.

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