Publications & Reports

Optimisation of 2-(N-phenyl carboxamide) triazolopyrimidine antimalarials with moderate to slow acting erythrocytic stage activity.

Bailey BL, Nguyen W, Ngo A, Goodman CD, Gancheva MR, Favuzza P, Sanz LM, Gamo FJ, Lowes KN, McFadden GI, Wilson DW, Laleu B, Brand S, Jackson PF, Cowman AF, Sleebs BE
The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.


Malaria is a devastating parasitic disease caused by parasites from the genus Plasmodium. Therapeutic resistance has been reported against all clinically available antimalarials, threatening our ability to control the disease and therefore there is an ongoing need for the development of novel antimalarials. Towards this goal, we identified the 2-(N-phenyl carboxamide) triazolopyrimidine class from a high throughput screen of the Janssen Jumpstarter library against the asexual stages of the P. falciparum parasite. Here we describe the structure activity relationship of the identified class and the optimisation of asexual stage activity while maintaining selectivity against the human HepG2 cell line. The most potent analogues from this study were shown to exhibit equipotent activity against P. falciparum multidrug resistant strains and P. knowlesi asexual parasites. Asexual stage phenotyping studies determined the triazolopyrimidine class arrests parasites at the trophozoite stage, but it is likely these parasites are still metabolically active until the second asexual cycle, and thus have a moderate to slow onset of action. Non-NADPH dependent degradation of the central carboxamide and low aqueous solubility was observed in in vitro ADME profiling. A significant challenge remains to correct these liabilities for further advancement of the 2-(N-phenyl carboxamide) triazolopyrimidine scaffold as a potential moderate to slow acting partner in a curative or prophylactic antimalarial treatment.

Link to publisher’s web site


  • Journal: Bioorganic Chemistry
  • Published: 08/08/2021
  • Volume: 115
  • Pagination: 105244


Health Issue