Synthesis and Antiprotozoal Activity of Dicationic m-Terphenyl and 1,3-Dipyridylbenzene Derivatives

4,4 ''-Diamidino-m-terphenyl (1) and 36 analogues were prepared and assayed in vitro against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Plasmodium falciparum, and Leishmania amazonensis. Twenty-three compounds were highly active,. against T. b. rhodesiense or P. falciparum. Most noteworthy were amidines 1, 10, and 11 with IC50 of 4 nM against T. b. rhodesiense and dimethyltetrahydropyrimidinyl analogues 4 and 9 with IC50 values of <= 3 nM against P. falciparum Bis-pyridylimidamide derivative 31 was 25 times more potent than benznidazole against T. cruzi and slightly more potent than amphotericin B against L. amazonensis. Terphenyldiamidine 1 and dipyridylbenzene analogues 23 and 25 each cured 4/4 mice infected with T. b., rhodesiense STIB900 with four daily 5 mg/kg intraperitoneal doses, as well as with single doses of <= 10 mg/kg. Derivatives 5 and 2(prodrugs of 1 and 25) each cured 3/4 mice with four dally 25 mg/kg oral doses.