Evaluation of 1,1-cyclopropylidene as a thioether isostere in the 4-thio-thienopyrimidine (TTP) series of antimalarials

Robert D. Barrows, Jared T. Hammill, Michael C. Tran, Mofolusho O. Falade, Amy L. Rice, Christopher W. Davis, Thomas J. Emge, Paul R. Rablen, R. Kiplin Guy, Spencer Knapp

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

The 4-(heteroarylthio)thieno[2,3-d]pyrimidine (TTP) series of antimalarials, represented by 1 and 17, potently inhibit proliferation of the 3D7 strain of P. falciparum (EC50 70–100 nM), but suffer from oxidative metabolism. The 1,1-cyclopropylidene isosteres 6 and 16 were designed to obviate this drawback. They were prepared by a short route that features a combined Peterson methylenation / cyclopropanation transformation of, e. g., ketone 7. Isosteres 6 and 16 possess significantly attenuated antimalarial potency relative to parents 1 and 17. This outcome can be rationalized based on the increased out-of-plane steric demands of the latter two. In support of this hypothesis, the relatively flat ketone 7 retains some of the potency of 1, even though it appears to be a comparatively inferior mimic with respect to electronics and bond lengths and angles. We also demonstrate crystallographically and computationally an apparent increase in the strength of the intramolecular sulfur hole interaction of 1 upon protonation.

Original languageEnglish
Article number115758
JournalBioorganic and Medicinal Chemistry
Volume28
Issue number22
DOIs
StatePublished - Nov 15 2020

Bibliographical note

Publisher Copyright:
© 2020

Keywords

  • Ab initio calculations
  • CoA synthesis
  • Cytochrome P450
  • Malaria
  • Sulfur hole

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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