Pharmacomodulation on the 3-acetylursolic acid skeleton: Design, synthesis, and biological evaluation of novel N-{3-[4-(3-aminopropyl)piperazinyl]propyl}-3-O-acetylursolamide derivatives as antimalarial agents

Bioorg Med Chem. 2008 Jan 15;16(2):771-82. doi: 10.1016/j.bmc.2007.10.031. Epub 2007 Oct 14.

Abstract

A series of new piperazine derivatives of ursolic acid was synthesized and tested against Plasmodium falciparum strains. They were also tested on their cytotoxicity effects upon MRC-5 cells. Seven new piperazinyl analogues showed significant activity in the nanomolar range (IC(50)=78-167nM) against Plasmodium falciparum CQ-resistant strain FcB1. A possible mechanism of interaction implicating binding of these compounds to beta-hematin was supported by in vitro tests. Moreover, the importance of the hydrophilic framework attached at the terminal nitrogen atom of the bis-(3-aminopropyl)piperazine joined to the triterpene ring was also explored through molecular dynamic simulations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimalarials* / chemical synthesis
  • Antimalarials* / chemistry
  • Antimalarials* / pharmacokinetics
  • Antimalarials* / pharmacology
  • Combinatorial Chemistry Techniques
  • Ilex paraguariensis / chemistry
  • Inhibitory Concentration 50
  • Molecular Structure
  • Parasitic Sensitivity Tests
  • Piperazines* / chemical synthesis
  • Piperazines* / chemistry
  • Piperazines* / pharmacokinetics
  • Piperazines* / pharmacology
  • Plants, Medicinal / chemistry
  • Plasmodium falciparum / drug effects*
  • Structure-Activity Relationship
  • Triterpenes* / chemical synthesis
  • Triterpenes* / chemistry
  • Triterpenes* / pharmacokinetics
  • Triterpenes* / pharmacology
  • Ursolic Acid

Substances

  • Antimalarials
  • Piperazines
  • Triterpenes