Synthesis and antiparasitic activity of new bis-arylimidamides : DB766 analogs modified in the terminal groups

Abstract Fifteen novel bis-arylimidamide derivatives with various 6-membered ( 7a – c ) and 5-membered ( 7d – o) heterocyclic rings replacing the terminal pyridyl rings of the lead compound DB766{(2,5-bis[2- i -propoxy-4-(2-pyridylimino)aminophenylfuran]}, were prepared and evaluated versus Trypanosoma cruzi , Leishmania amazonensis , Trypanosoma brucei rhodesiense and Plasmodium falciparum . Compound 7a with pyrimidine replacing the pyridine rings showed good activity versus T. cruzi , T. brucei rhodesiense and P. falciparum (IC 50  = 200 nM, 32 nM and 8.5 nM, respectively). Three compounds ( 7g , 7i , 7j ) with thiazole replacing the pyridine rings gave low micromolar (0.17–0.3 μM) IC 50 values versus L. amazonensis , however only 7g exhibited an acceptable selectivity index (SI = 27). Compounds 7a , 7j and 7m exhibited potent activity against T. brucei rhodesiense (IC 50  = 12–60 nM). Ten of the 15 compounds with pyrimidine, pyrrole, thiazole and imidazole terminal units were highly active against P. falciparum (IC 50  = 9–87 nM). Both pyrimidine and pyridine terminal groups are advantageous for anti- T. cruzi activity and several different heterocyclic terminal units are effective versus P. falciparum, both findings merit further investigation.