Mixed steroidal 1,2,4,5-tetraoxanes: antimalarial and antimycobacterial activity.
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.
Faculty of Chemistry, University of Belgrade, 11001 Belgrade, Yugoslavia. bsolaja@chem.bg.ac.yu
Bogdan A
BA
Solaja
Natasa
N
Terzić
Gabriella
G
Pocsfalvi
Lucia
L
Gerena
Bernard
B
Tinant
Dejan
D
Opsenica
Wilbur K
WK
Milhous
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D000962:Antimalarials / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects; D021241:Spectrometry, Mass, Electrospray Ionization; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D013256:Steroids / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship; D014709:Vero Cells
D000900:Anti-Bacterial Agents; D000962:Antimalarials; D013141:Spiro Compounds; D013256:Steroids