Antimalarial and antitubercular nostocarboline and eudistomin derivatives: synthesis, in vitro and in vivo biological evaluation.

The synthesis of nine nostocarboline derivatives with substitutions of the 2-methyl group by alkyl, aryl and functionalized residues, 10 symmetrical bis cationic dimers linking 6-Cl-norharmane through the 2-position and fifteen derivatives of the marine alkaloids eudistomin N and O is reported. These compounds were evaluated in vitro against four parasites (Trypanosoma brucei rhodesiense STIB 900, Trypanosoma cruzi Tulahuen C2C4, Leishmania donovani MHOM-ET-67/L82 axenic amastigotes, and Plasmodium falciparum K1 strain), against Mycobacterium tuberculosis H37Rv, Mycobacterium smegmatis mc(2)155 and Corynebacterium glutamicum ATCC13032, and cytotoxicity was determined against L6 rat myoblast cells. Nostocarboline and derivatives displayed potent and selective in vitro inhibition of P. falciparum with weak cytotoxicity. The dimers displayed submicromolar inhibition of L. donovani and T. brucei, and nanomolar activity against P. falciparum, albeit with pronounced cytotoxicity. One dimer showed a MIC(99) value against M. tuberculosis of 2.5 microg/ml. The alkylated eudistomin N and O derivatives displayed activities down to 18 nM against P. falciparum for N-Me Eudistomin N. Four dimers, nostocarboline and three eudostomin derivatives were evaluated in an in vivo Plasmodium berghei mouse model. No significant activity was observed for the dimers, but a 50% reduction in parasitaemia was observed at 4 x 50 mg/kg ip for nostocarboline.
AuthorsSimone Bonazzi, Damien Barbaras, Luc Patiny, Rosario Scopelliti, Patricia Schneider, Stewart T Cole, Marcel Kaiser, Reto Brun, Karl Gademann
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 18 Issue 4 Pg. 1464-76 (Feb 15 2010) ISSN: 1464-3391 [Electronic] England
PMID20133138 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright 2010 Elsevier Ltd. All rights reserved.
Chemical References
  • Antimalarials
  • Antitubercular Agents
  • Carbolines
  • nostocarboline
  • Animals
  • Antimalarials (chemical synthesis, chemistry, pharmacology)
  • Antitubercular Agents (chemical synthesis, chemistry, pharmacology)
  • Carbolines (chemical synthesis, chemistry, pharmacology)
  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical
  • In Vitro Techniques
  • Leishmania donovani (drug effects)
  • Magnetic Resonance Spectroscopy
  • Mycobacterium (drug effects)
  • Plasmodium falciparum (drug effects)
  • Rats
  • Spectroscopy, Fourier Transform Infrared
  • Trypanosoma (drug effects)

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