Structurally simple, potent, Plasmodium selective farnesyltransferase inhibitors that arrest the growth of malaria parasites

Matthew P. Glenn, Sung Youn Chang, Carrie Hornéy, Kasey Rivas, Kohei Yokoyama, Erin E. Pusateri, Steven Fletcher, Christopher G. Cummings, Frederick S. Buckner, Prakash R. Pendyala, Debopam Chakrabarti, Saïd M. Sebti, Michael Gelb, Wesley C. Van Voorhis, Andrew D. Hamilton

Research output: Contribution to journalArticle

Abstract

Third world nations require immediate access to inexpensive therapeutics to counter the high mortality inflicted by malaria. Here, we report a new class of antimalarial protein farnesyltransferase (PFT) inhibitors, designed with specific emphasis on simple molecular architecture, to facilitate easy access to therapies based on this recently validated antimalarial target. This novel series of compounds represents the first Plasmodium falciparum selective PFT inhibitors reported (up to 145-fold selectivity), with lead inhibitors displaying excellent in vitro activity (IC50 < 1 nM) and toxicity to cultured parasites at low concentrations (ED50 < 100 nM). Initial studies of absorption, metabolism, and oral bioavailability are reported.

Original languageEnglish (US)
Pages (from-to)5710-5727
Number of pages18
JournalJournal of Medicinal Chemistry
Volume49
Issue number19
DOIs
StatePublished - Sep 21 2006

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Glenn, M. P., Chang, S. Y., Hornéy, C., Rivas, K., Yokoyama, K., Pusateri, E. E., Fletcher, S., Cummings, C. G., Buckner, F. S., Pendyala, P. R., Chakrabarti, D., Sebti, S. M., Gelb, M., Van Voorhis, W. C., & Hamilton, A. D. (2006). Structurally simple, potent, Plasmodium selective farnesyltransferase inhibitors that arrest the growth of malaria parasites. Journal of Medicinal Chemistry, 49(19), 5710-5727. https://doi.org/10.1021/jm060081v