Bis(benzyl)polyamine analogs inhibit the growth of chloroquine- resistant human malaria parasites (Plasmodium falciparum) in vitro and in combination with a-difluoromethylornithine

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 para- site Plasmodiumfalciparum in vitro (IC50 values = 0.2-14 ,uM). Administration of one of the compounds, MDL 27695, which is N,N'-bis{3-((phenylmethyl)amino)propyl}-1,7-diaminohep- tane (C6HsCH2NH(CH2)3NH(CH2)7NH(CH2)3NHCH2C6Hs), at 10-15 mg/kg i.p. three times per day for 3 days in com- bination with 2% a-difluoromethylornithine (DFMO; eflorni- thine) 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 con- clude, 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.