Bis(benzyl)polyamine analogs inhibit the growth of chloroquine-resistant human malaria parasites (Plasmodium falciparum) in vitro and in combination with alpha-difluoromethylornithine cure murine malaria.
A number of bis(benzyl)polyamine analogs were found to be potent inhibitors of both chloroquine-resistant and chloroquine-sensitive strains of the human malaria parasite Plasmodium falciparum in vitro (IC50 values = 0.2-14 microM). Administration of one of the compounds, MDL 27695, which is N,N'-bis(3-[(phenylmethyl)amino]propyl)-1,7-diaminoheptane (C6H5CH2NH(CH2)3NH(CH2)7NH(CH2)3NHCH2C6H5), at 10-15 mg/kg i.p. three times per day for 3 days in combination with 2% alpha-difluoromethylornithine (DFMO; eflornithine) in drinking water effected cures of 47/54 mice infected with Plasmodium berghei. Cured mice were found to be immune upon rechallenge with the same P. berghei strain 4 months after the initial infection and drug-induced cure. MDL 27695 rapidly inhibited the incorporation of [3H]hypoxanthine into P. falciparum RNA and DNA, whereas the incorporation of [3H]isoleucine was not affected until much later. We conclude, therefore, that the major cytotoxic event may be direct binding of MDL 27695 to DNA with subsequent disruption of macromolecular biosynthesis and cell death. These compounds offer a lead in the search for new agents for chemotherapy of malaria.
Bitonti
A J
AJ
Merrell Dow Research Institute, Cincinnati, OH 45215.
Dumont
J A
JA
Bush
T L
TL
Edwards
M L
ML
Stemerick
D M
DM
McCann
P P
PP
Sjoerdsma
A
A
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D002738:Chloroquine / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D000518:Eflornithine / Q000627:therapeutic use*; D006801:Humans; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011073:Polyamines / Q000494:pharmacology* / Q000627:therapeutic use; D014176:Protein Biosynthesis; D012313:RNA / Q000096:biosynthesis
D000962:Antimalarials; D011073:Polyamines; C058294:MDL 27695; D012313:RNA; D002738:Chloroquine; D004247:DNA; D000518:Eflornithine