Mixed steroidal 1,2,4,5-tetraoxanes: antimalarial and antimycobacterial activity

J Med Chem. 2002 Aug 1;45(16):3331-6. doi: 10.1021/jm020891g.


Mixed 1,2,4,5-tetraoxanes possessing simple spirocycloalkane and spirocholic acid-derived substituents were prepared and shown to have significantly higher in vitro antimalarial activity than bis-substituted tetraoxanes. Out of 41 synthesized tetraoxanes, 12 were in vitro more potent against Plasmodium falciparum chloroquine-resistant W2 clone than artemisinin, and the most potent one was 2.4 times as active as arteether. In addition, 9 compounds exhibit higher activity than chloroquine against P. falciparum chloroquine-susceptible D6 clone. Cytotoxicity was assessed for most active compounds against the Vero cell line, showing a cytotoxicity/antimalarial potency ratio of 1/(1400-9500). For the first time, tetraoxanes were screened against Mycobacterium tuberculosis with MICs as low as 4.73 microM against H37Rv strain. Mixed tetraoxanes were synthesized in a simple procedure from cholic acid methyl esters by direct coupling of steroidal gem-dihydroperoxide to simple ketones and further transformed into corresponding acids and amides.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / toxicity
  • Antimalarials / chemical synthesis
  • Antimalarials / pharmacology
  • Antimalarials / toxicity
  • Chlorocebus aethiops
  • Crystallography, X-Ray
  • Inhibitory Concentration 50
  • Microbial Sensitivity Tests
  • Mycobacterium tuberculosis / drug effects*
  • Plasmodium falciparum / drug effects
  • Spectrometry, Mass, Electrospray Ionization
  • Spiro Compounds / chemical synthesis*
  • Spiro Compounds / pharmacology
  • Spiro Compounds / toxicity
  • Steroids / chemical synthesis*
  • Steroids / pharmacology
  • Steroids / toxicity
  • Structure-Activity Relationship
  • Vero Cells


  • Anti-Bacterial Agents
  • Antimalarials
  • Spiro Compounds
  • Steroids