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  • Title: Dicationic DNA-targeted antiprotozoal agents: naphthalene replacement of benzimidazole.
    Author: Chackal-Catoen S, Miao Y, Wilson WD, Wenzler T, Brun R, Boykin DW.
    Journal: Bioorg Med Chem; 2006 Nov 15; 14(22):7434-45. PubMed ID: 16889966.
    Abstract:
    A series of naphthalene analogues of highly active benzimidazole diamidines were synthesized using sequential Stille and Suzuki coupling reactions for preparation of the bis-nitrile intermediates. All of the diamidines showed strong DNA affinities as judged by high DeltaTm values with poly(dA-dT). The dicationic compounds were quite active in vitro versus Trypanosoma brucei rhodesiense (T. b. r.) exhibiting IC50 values ranging from 4 to 98 nM. These compounds were also active versus Plasmodium falciparum (P. f.) giving IC50 values ranging from 4 to 33 nM. Two of the compounds showed good activity in vivo in the STIB900 model for acute African trypanosomiasis; one gave 3/4 cures and the other gave 4/4 cures on ip dosage of 20 mg/kg for 4 days. The amidoxime prodrugs of the naphthalene analogues were essentially ineffective.
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