Synthesis and antiplasmodial activity of bisindolylcyclobutenediones

Duc Hoàng Lande, Abed Nasereddin, Arne Alder, Tim W. Gilberger, Ron Dzikowski, Johann Grünefeld, Conrad Kunick*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Malaria is one of the most dangerous infectious diseases. Because the causative Plasmod-ium parasites have developed resistances against virtually all established antimalarial drugs, novel antiplasmodial agents are required. In order to target plasmodial kinases, novel N-unsubstituted bisindolylcyclobutenediones were designed as analogs to the kinase inhibitory bisindolylmaleimides. Molecular docking experiments produced favorable poses of the unsubstituted bisindolylcyclobutene-dione in the ATP binding pocket of various plasmodial protein kinases. The synthesis of the title compounds was accomplished by sequential Friedel-Crafts acylation procedures. In vitro screening of the new compounds against transgenic NF54-luc P. falciparum parasites revealed a set of derivatives with submicromolar activity, of which some displayed a reasonable selectivity profile against a human cell line. Although the molecular docking studies suggested the plasmodial protein kinase Pf GSK-3 as the putative biological target, the title compounds failed to inhibit the isolated enzyme in vitro. As selective submicromolar antiplasmodial agents, the N-unsubstituted bisindolylcyclobutenediones are promising starting structures in the search for antimalarial drugs, albeit for a rational development, the biological target addressed by these compounds has yet to be identified.

Original languageAmerican English
Article number4739
Issue number16
StatePublished - 5 Aug 2021

Bibliographical note

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.


  • Bisindolylmaleimide
  • Cyclobutenedione
  • Drug design
  • Drug screening
  • Friedel-Crafts reaction
  • Glycogen synthase kinase-3
  • Indole
  • Malaria
  • Molecular docking
  • Plasmodium


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