Nonbisphosphonate inhibitors of Plasmodium falciparum FPPS/GGPPS

Bioorg Med Chem Lett. 2021 Jun 1:41:127978. doi: 10.1016/j.bmcl.2021.127978. Epub 2021 Mar 22.

Abstract

A series of novel thiazole-containing amides were synthesized. A structure-activity relationship study of these compounds led to the identification of potent and selective PfFPPS/GGPPS inhibitors with good in vitro ADME profiles. The most promising candidate molecules were progressed to mouse in vivo PK studies and demonstrated adequate free drug exposure to warrant further investigation.

Keywords: Farnesyl/Geranylgeranyl diphosphate synthase; Malaria; Plasmodium falciparum; SAR; Thiazole.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / chemical synthesis
  • Antimalarials / chemistry
  • Antimalarials / pharmacology*
  • Diphosphonates / chemical synthesis
  • Diphosphonates / chemistry
  • Diphosphonates / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Farnesyltranstransferase / antagonists & inhibitors*
  • Farnesyltranstransferase / metabolism
  • Geranyltranstransferase / antagonists & inhibitors*
  • Geranyltranstransferase / metabolism
  • Molecular Structure
  • Parasitic Sensitivity Tests
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / enzymology
  • Structure-Activity Relationship

Substances

  • Antimalarials
  • Diphosphonates
  • Enzyme Inhibitors
  • Geranyltranstransferase
  • Farnesyltranstransferase