Structure-activity relationship studies on thiaplidiaquinones A and B as novel inhibitors of Plasmodium falciparum and farnesyltransferase

Bioorg Med Chem. 2017 Aug 15;25(16):4433-4443. doi: 10.1016/j.bmc.2017.06.029. Epub 2017 Jun 19.

Abstract

Marine meroterpenoids, thiaplidiaquinones A and B and their respective non-natural dioxothiazine regioisomers have been shown to inhibit mammalian and protozoal farnesyltransferase (FTase) with the regioisomers exhibiting activity in the nanomolar range. In order to explore the structure-activity relationship (SAR) of this class of marine natural products, analogues of thiaplidiaquinones A and B and their regioisomers were synthesised, with variation in the number of isoprene units present in their side chains to afford prenyl and farnesyl analogues. The previously reported geranyl series of compounds were found to be the most potent FTase inhibitors closely followed by the novel farnesyl series. The prenyl series exhibited the most potent anti-plasmodial activity but the series was also the most cytotoxic. Overall, the farnesyl series exhibited moderate anti-plasmodial activity with one analogue, 14 also exhibiting low cytotoxicity, identifying it as a scaffold worthy of further exploration.

Keywords: Anti-plasmodial; Biomimetic; FTase inhibitor; Natural product; Thiaplidiaquinone.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Antimalarials / chemical synthesis
  • Antimalarials / chemistry
  • Antimalarials / pharmacology*
  • Cell Line
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Farnesyltranstransferase / antagonists & inhibitors*
  • Farnesyltranstransferase / metabolism
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / enzymology
  • Rats
  • Staphylococcus / classification
  • Staphylococcus / drug effects*
  • Structure-Activity Relationship
  • Terpenes / chemical synthesis
  • Terpenes / chemistry
  • Terpenes / pharmacology*

Substances

  • Anti-Bacterial Agents
  • Antimalarials
  • Terpenes
  • thiaplidiaquinone A
  • thiaplidiaquinone B
  • Farnesyltranstransferase