Structure-activity relationship of antiparasitic and cytotoxic indoloquinoline alkaloids, and their tricyclic and bicyclic analogues

Gitte Van Baelen, Steven Hostyn, Liene Dhooghe, Pál Tapolcsányi, Péter Mátyus, Guy Lemière, Roger Dommisse, Marcel Kaiser, Reto Brun, Paul Cos, Louis Maes, György Hajós, Zsuzsanna Riedl, Ildikó Nagy, Bert U.W. Maes, Luc Pieters

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52 Citations (Scopus)

Abstract

Based on the indoloquinoline alkaloids cryptolepine (1), neocryptolepine (2), isocryptolepine (3) and isoneocryptolepine (4), used as lead compounds for new antimalarial agents, a series of tricyclic and bicyclic analogues, including carbolines, azaindoles, pyrroloquinolines and pyrroloisoquinolines was synthesized and biologically evaluated. None of the bicyclic compounds was significantly active against the chloroquine-resistant strain Plasmodium falciparum K1, in contrast to the tricyclic derivatives. The tricyclic compound 2-methyl-2H-pyrido[3,4-b]indole (9), or 2-methyl-β-carboline, showed the best in vitro activity, with an IC50 value of 0.45 μM against P. falciparum K1, without apparent cytotoxicity against L6 cells (SI > 1000). However, this compound was not active in the Plasmodium berghei mouse model. Structure-activity relationships are discussed and compared with related naturally occurring compounds.

Original languageEnglish
Pages (from-to)7209-7217
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number20
DOIs
Publication statusPublished - Oct 15 2009

Keywords

  • Antimalarial
  • Antiparasitic
  • Antiplasmodial
  • Azaindole
  • Carboline
  • Cytotoxic
  • Indoloisoquinoline
  • Indoloquinoline alkaloid
  • Pyrroloisoquinoline
  • Pyrroloquinoline

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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  • Cite this

    Van Baelen, G., Hostyn, S., Dhooghe, L., Tapolcsányi, P., Mátyus, P., Lemière, G., Dommisse, R., Kaiser, M., Brun, R., Cos, P., Maes, L., Hajós, G., Riedl, Z., Nagy, I., Maes, B. U. W., & Pieters, L. (2009). Structure-activity relationship of antiparasitic and cytotoxic indoloquinoline alkaloids, and their tricyclic and bicyclic analogues. Bioorganic and Medicinal Chemistry, 17(20), 7209-7217. https://doi.org/10.1016/j.bmc.2009.08.057