Synthesis and Antiprotozoal Activity of Cationic 1,4-Diphenyl-1 H -1,2,3-triazoles

Novel dicationic triazoles 1–60 were synthesized by the Pinner method from the corresponding dinitriles, prepared via the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The type and the placement of cationic moieties as well as the nature of aromatic substituents influenced in vitro antiprotozoal activities of compounds 1–60 against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani and their cytotoxicity for mammalian cells. Eight congeners displayed antitrypanosomal IC50 values below 10 nM. Thirty-nine dications were more potent against P. falciparum than pentamidine (IC50 = 58 nM) and eight analogues were more active than artemisinin (IC50 = 6 nM). Diimidazoline 60 exhibited antiplasmodial IC50 value of 0.6 nM. Seven congeners administered at 4 × 5 mg/kg by the intraperitoneal route cured at least three out of four animals in the acute mouse model of African trypanosomiasis. At 4 × 1 mg/kg, diamidine 46 displayed better antitrypanosomal efficacy than melarsoprol, curing all infected mice