Antiplasmodial dihetarylthioethers target the coenzyme A synthesis pathway in Plasmodium falciparum erythrocytic stages

Thomas Weidner, Leonardo Lucantoni, Abed Nasereddin, Lutz Preu, Peter G. Jones, Ron Dzikowski, Vicky M. Avery, Conrad Kunick*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Background: Malaria is a widespread infectious disease that threatens a large proportion of the population in tropical and subtropical areas. Given the emerging resistance against the current standard anti-malaria chemotherapeutics, the development of alternative drugs is urgently needed. New anti-malarials representing chemotypes unrelated to currently used drugs have an increased potential for displaying novel mechanisms of action and thus exhibit low risk of cross-resistance against established drugs. Results: Phenotypic screening of a small library (32 kinase-inhibitor analogs) against Plasmodium falciparum NF54-luc asexual erythrocytic stage parasites identified a diarylthioether structurally unrelated to registered drugs. Hit expansion led to a series in which the most potent congener displayed nanomolar antiparasitic activity (IC50 = 39 nM, 3D7 strain). Structure-activity relationship analysis revealed a thieno[2,3-d]pyrimidine on one side of the thioether linkage as a prerequisite for antiplasmodial activity. Within the series, the oxazole derivative KuWei173 showed high potency (IC50 = 75 nM; 3D7 strain), good solubility in aqueous solvents (1.33 mM), and >100-fold selectivity toward human cell lines. Rescue experiments identified inhibition of the plasmodial coenzyme A synthesis as a possible mode of action for this compound class. Conclusions: The class of antiplasmodial bishetarylthioethers reported here has been shown to interfere with plasmodial coenzyme A synthesis, a mechanism of action not yet exploited for registered anti-malarial drugs. The oxazole congener KuWei173 displays double-digit nanomolar antiplasmodial activity, selectivity against human cell lines, high drug likeness, and thus represents a promising chemical starting point for further drug development.

Original languageAmerican English
Article number192
JournalMalaria Journal
Issue number1
StatePublished - 15 May 2017

Bibliographical note

Funding Information:
The project was funded by the German Federal Ministry of Education and Research (BMBF BioDisc 7; 13GW0024) awarded to RD and CK and an Australian Research Council LP120200557 awarded to VMA. Support by the COST action CM1307 “Targeted chemotherapy towards diseases caused by endoparasites”(to TW and CK) is gratefully acknowledged. We thank the Australian Red Cross Blood Bank for the provision of human red blood cells.

Publisher Copyright:
© 2017 The Author(s).


  • 1,3,4-Oxadiazole
  • Anti-malaria drugs
  • Coenzyme A synthesis
  • Drug discovery
  • Malaria
  • Oxazole
  • Phenotypic screening
  • Plasmodium falciparum
  • Thieno[2,3-d]pyrimidine
  • Thioether


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