Biologically active derivatives of gossypol: synthesis and antimalarial activities of peri-acylated gossylic nitriles.
A series of peri-acylated gossylic nitriles were synthesized from gossypol dioxime by treatment of the dioxime with the appropriate acid anhydride and its salt. The reaction pathway was elucidated by isolation and characterization of intermediates. Peri-acylated gossylic nitriles (acyl = acetyl, propionyl, butyryl, and valeryl) were compared with gossypol for activity against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. The gossylic nitriles all retain activity, with activity increasing with the length of the peri-acyl group. Gossylic nitrile 1,1'-divalerate shows antimalarial activity comparable to gossypol itself. The peri-acylated gossylic nitriles are strong inhibitors of parasite lactate dehydrogenase.
D000215:Acylation; D055598:Chemical Phenomena; D002621:Chemistry; D002738:Chloroquine / Q000494:pharmacology; D004351:Drug Resistance; D006072:Gossypol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors; D009570:Nitriles / Q000138:chemical synthesis / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology
D009570:Nitriles; D002738:Chloroquine; D007770:L-Lactate Dehydrogenase; D006072:Gossypol