Synthesis and Antimalarial Activities of a Diverse Set of Triazole-Containing Furamidine Analogues

Four different series of triazole diamidines have been prepared by the Pinner method from the corresponding triazole dinitriles. Copper‐catalyzed “click chemistry” was used for the synthesis of 1,4‐ and 4,5‐substituted triazoles, aryl magnesium acetylide reagents for the 1,5‐substituted triazoles, with a thermal dipolar addition reaction employed for the 2,4‐substituted triazoles. In vitro antimalarial activity against two different PfCRT‐modified parasite lines (Science 2002, 298, 210–213) of Plasmodium falciparum and inhibition of hemozoin formation were determined for each compound. Several diamidines with potent nanomolar antimalarial activities were identified, and selected molecules were resynthesized as their diamidoxime triazole prodrugs. One of these prodrugs, OB216, proved to be highly potent in vivo with an ED50 value of 5 mg kg−1 (po) and an observed 100 % cure rate (CD100) of just 10 mg kg−1 by oral (po) administration in mice infected with P. vinckei. Diverse triazoles: Sixteen different triazoles were prepared to probe the antimalarial structure–activity relationships (SAR) within the triazole diamidine family. Two of these series, OB076 and OB125, have nanomolar in vitro activity against human Plasmodium falciparum and potent in vivo activity against the rodent parasite P. vinckei; their prodrugs (OB216 and OB135, respectively) are capable of achieving complete cure at doses of less than 30 mg kg−1, and a promising lead compound (CD100=10 mg kg−1) was identified for further studies.