posted on 2019-01-07, 00:00authored byFrancesco Saccoliti, Valentina Noemi Madia, Valeria Tudino, Alessandro De Leo, Luca Pescatori, Antonella Messore, Daniela De Vita, Luigi Scipione, Reto Brun, Marcel Kaiser, Pascal Mäser, Claudia M. Calvet, Gareth K. Jennings, Larissa M. Podust, Giacomo Pepe, Roberto Cirilli, Cristina Faggi, Annalise Di Marco, Maria Rosaria Battista, Vincenzo Summa, Roberta Costi, Roberto Di Santo
We have designed and synthesized
a series of new imidazole-based
compounds structurally related to an antiprotozoal agent with nanomolar
activity which we identified recently. The new analogues possess micromolar
activities against Trypanosoma brucei rhodesiense and Leishmania donovani and nanomolar
potency against Plasmodium falciparum. Most of the analogues displayed IC50 within the low
nanomolar range against Trypanosoma cruzi, with very high selectivity toward the parasite. Discussion of structure–activity
relationships and in vitro biological data for the new compounds are
provided against a number of different protozoa. The mechanism of
action for the most potent derivatives (5i, 6a–c, and 8b) was assessed by a target-based assay using
recombinant T. cruzi CYP51. Bioavailability
and efficacy of selected hits were assessed in a T.
cruzi mouse model, where 6a and 6b reduced parasitemia in animals >99% following intraperitoneal
administration of 25 mg/kg/day dose for 4 consecutive days.