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Synthesis and Antimalarial Activities of a Diverse Set of Triazole‐Containing Furamidine Analogues
Author(s) -
Berger Olivier,
Kaniti Archana,
van Ba Christophe Tran,
Vial Henri,
Ward Stephen A.,
Biagini Giancarlo A.,
Bray Patrick G.,
O'Neill Paul M.
Publication year - 2011
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100265
Subject(s) - prodrug , triazole , chemistry , acetylide , click chemistry , combinatorial chemistry , in vivo , plasmodium falciparum , hemozoin , in vitro , reagent , stereochemistry , biochemistry , organic chemistry , biology , enzyme , heme , microbiology and biotechnology , malaria , immunology
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 ED 50 value of 5 mg kg −1 (po) and an observed 100 % cure rate (CD 100 ) of just 10 mg kg −1 by oral (po) administration in mice infected with P. vinckei .