Structure-activity analysis of CJ-15,801 analogues that interact with Plasmodium falciparum pantothenate kinase and inhibit parasite proliferation

Christina Spry, Alan L. Sewell, Yuliya Hering, Mathew V.J. Villa, Jonas Weber, Stephen J. Hobson, Suzannah J. Harnor, Sheraz Gul, Rodolfo Marquez, Kevin J. Saliba*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

Survival of the human malaria parasite Plasmodium falciparum is dependent on pantothenate (vitamin B5), a precursor of the fundamental enzyme cofactor coenzyme A. CJ-15,801, an enamide analogue of pantothenate isolated from the fungus Seimatosporium sp. CL28611, was previously shown to inhibit P. falciparum proliferation in vitro by targeting pantothenate utilization. To inform the design of next generation analogues, we set out to synthesize and test a series of synthetic enamide-bearing pantothenate analogues. We demonstrate that conservation of the R-pantoyl moiety and the trans-substituted double bond of CJ-15,801 is important for the selective, on-target antiplasmodial effect, while replacement of the carboxyl group is permitted, and, in one case, favored. Additionally, we show that the antiplasmodial potency of CJ-15,801 analogues that retain the R-pantoyl and trans-substituted enamide moieties correlates with inhibition of P. falciparum pantothenate kinase (PfPanK)-catalyzed pantothenate phosphorylation, implicating the interaction with PfPanK as a key determinant of antiplasmodial activity.

Original languageEnglish
Pages (from-to)1139-1147
Number of pages9
JournalEuropean Journal of Medicinal Chemistry
Volume143
DOIs
Publication statusPublished - 1 Jan 2018

Keywords

  • Antimalarial
  • CJ-15,801
  • Pantothenate
  • Pantothenate kinase
  • Plasmodium falciparum

Fingerprint

Dive into the research topics of 'Structure-activity analysis of CJ-15,801 analogues that interact with Plasmodium falciparum pantothenate kinase and inhibit parasite proliferation'. Together they form a unique fingerprint.

Cite this