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 analogs possess micromolar activities against T. b. rhodesiense and L. donovani and nanomolar potency against P. falciparum. Most of the analogs displayed the IC50 within the low nanomolar range against T. cruzi, with very high selectivity towards 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, 8b) was assessed by a target-based assays using recombinant T. cruzi CYP51. Bioavailability and efficacy of selected hits was 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 four consecutive days.

Design, synthesis, and biological evaluation of new 1-(aryl-1H-pyrrolyl)(phenyl)methyl-1H-imidazole derivatives as antiprotozoal agents / Saccoliti, Francesco; Madia, Valentina Noemi; Tudino, Valeria; De Leo, Alessandro; Pescatori, Luca; Messore, Antonella; De Vita, Daniela; Scipione, Luigi; Brun, Reto; Kaiser, Marcel; Mäser, Pascal; Calvet Alvarez, Claudia Magalhaes; Jennings, Gareth K; Podust, Larissa M; Pepe, Giacomo; Cirilli, Roberto; Faggi, Cristina; Di Marco, Annalise; Battista, Maria Rosaria; Summa, Vincenzo; Costi, Roberta; Di Santo, Roberto. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 62:(2019), pp. 1330-1347. [10.1021/acs.jmedchem.8b01464]

Design, synthesis, and biological evaluation of new 1-(aryl-1H-pyrrolyl)(phenyl)methyl-1H-imidazole derivatives as antiprotozoal agents

Saccoliti, Francesco
Primo
;
Madia, Valentina Noemi
Secondo
;
Tudino, Valeria;De Leo, Alessandro;Pescatori, Luca;Messore, Antonella;De Vita, Daniela;Scipione, Luigi;Costi, Roberta
Penultimo
;
Di Santo, Roberto
Ultimo
2019

Abstract

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 analogs possess micromolar activities against T. b. rhodesiense and L. donovani and nanomolar potency against P. falciparum. Most of the analogs displayed the IC50 within the low nanomolar range against T. cruzi, with very high selectivity towards 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, 8b) was assessed by a target-based assays using recombinant T. cruzi CYP51. Bioavailability and efficacy of selected hits was 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 four consecutive days.
2019
antiprotozoal; CYP51; imidazole
01 Pubblicazione su rivista::01a Articolo in rivista
Design, synthesis, and biological evaluation of new 1-(aryl-1H-pyrrolyl)(phenyl)methyl-1H-imidazole derivatives as antiprotozoal agents / Saccoliti, Francesco; Madia, Valentina Noemi; Tudino, Valeria; De Leo, Alessandro; Pescatori, Luca; Messore, Antonella; De Vita, Daniela; Scipione, Luigi; Brun, Reto; Kaiser, Marcel; Mäser, Pascal; Calvet Alvarez, Claudia Magalhaes; Jennings, Gareth K; Podust, Larissa M; Pepe, Giacomo; Cirilli, Roberto; Faggi, Cristina; Di Marco, Annalise; Battista, Maria Rosaria; Summa, Vincenzo; Costi, Roberta; Di Santo, Roberto. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 62:(2019), pp. 1330-1347. [10.1021/acs.jmedchem.8b01464]
File allegati a questo prodotto
File Dimensione Formato  
Saccoliti_Design-synthesis_2019.pdf

solo gestori archivio

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 1.54 MB
Formato Adobe PDF
1.54 MB Adobe PDF   Contatta l'autore

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1222183
Citazioni
  • ???jsp.display-item.citation.pmc??? 8
  • Scopus 31
  • ???jsp.display-item.citation.isi??? 29
social impact