Theoretical and experimental studies of new modified isoflavonoids as potential inhibitors of topoisomerase I from Plasmodium falciparum

PLoS One. 2014 Mar 20;9(3):e91191. doi: 10.1371/journal.pone.0091191. eCollection 2014.


DNA topoisomerase I from Plasmodium falciparum (PfTopoI), a potential selective target for chemotherapy and drug development against malaria, is used here, together with human Topo I (HssTopoI), for docking, molecular dynamics (MD) studies and experimental assays. Six synthetic isoflavonoid derivatives and the known PfTopoI inhibitors camptothecin and topotecan were evaluated in parallel. Theoretical results suggest that these compounds dock in the binding site of camptothecin and topotecan inside both enzymes and that LQB223 binds selectively in PfTopoI. In vitro tests against P. falciparum blood parasites corroborated the theoretical findings. The selectivity index (SI) of LQB223 ≥ 98 suggests that this molecule is the most promising in the group of compounds tested. In vivo experiments in mice infected with P. berghei showed that LQB223 has an antimalarial activity similar to that of chloroquine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimalarials / chemistry
  • Antimalarials / pharmacology*
  • Antimalarials / therapeutic use
  • Camptothecin / chemistry
  • Camptothecin / pharmacology
  • Crystallography, X-Ray
  • DNA Topoisomerases, Type I / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Resistance / drug effects
  • Female
  • Humans
  • Inhibitory Concentration 50
  • Isoflavones / chemistry
  • Isoflavones / pharmacology*
  • Isoflavones / therapeutic use
  • Malaria, Falciparum / drug therapy
  • Malaria, Falciparum / parasitology
  • Mice
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Parasites / drug effects
  • Plasmodium berghei / drug effects
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / enzymology*
  • Thermodynamics
  • Topoisomerase Inhibitors / chemistry
  • Topoisomerase Inhibitors / pharmacology*
  • Topotecan / chemistry
  • Topotecan / pharmacology


  • Antimalarials
  • Isoflavones
  • Topoisomerase Inhibitors
  • Topotecan
  • DNA Topoisomerases, Type I
  • Camptothecin

Grant support

Funding provided by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)- 304557/2012-9 and Fundação de Amparo à Pesquisa do Rio de Janeiro (FAPERJ)- E-26/102.993/2012. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.