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2022-01-01
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DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF NEW 1-(ARYL-1 H-PYRROLYL)(PHENYL)METHYL-1 H-IMIDAZOLE DERIVATIVES AS ANTIPROTOZOAL AGENTS
Saccoliti, Francesco et al. | Date Issued: 2019
Author
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, Claudia M.
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
Affilliation
Istituto Pasteur-Fondazione Cenci Bolognetti. Dipartimento di Chimica e Tecnologie del Farmaco. “Sapienza” Università di Roma. Rome, Italy.
Istituto Pasteur-Fondazione Cenci Bolognetti. Dipartimento di Chimica e Tecnologie del Farmaco. “Sapienza” Università di Roma. Rome, Italy.
Istituto Pasteur-Fondazione Cenci Bolognetti. Dipartimento di Chimica e Tecnologie del Farmaco. “Sapienza” Università di Roma. Rome, Italy.
Istituto Pasteur-Fondazione Cenci Bolognetti. Dipartimento di Chimica e Tecnologie del Farmaco. “Sapienza” Università di Roma. Rome, Italy.
Istituto Pasteur-Fondazione Cenci Bolognetti. Dipartimento di Chimica e Tecnologie del Farmaco. “Sapienza” Università di Roma. Rome, Italy.
Istituto Pasteur-Fondazione Cenci Bolognetti. Dipartimento di Chimica e Tecnologie del Farmaco. “Sapienza” Università di Roma. Rome, Italy.
Istituto Pasteur-Fondazione Cenci Bolognetti. Dipartimento di Chimica e Tecnologie del Farmaco. “Sapienza” Università di Roma. Rome, Italy.
Istituto Pasteur-Fondazione Cenci Bolognetti. Dipartimento di Chimica e Tecnologie del Farmaco. “Sapienza” Università di Roma. Rome, Italy.
Swiss Tropical and Public Health Institute. Base, Switzerland.
Swiss Tropical and Public Health Institute. Base, Switzerland.
Swiss Tropical and Public Health Institute. Base, Switzerland.
Skaggs School of Pharmacy and Pharmaceutical Sciences. University of California San Diego. La Jolla, California, USA / Fundação Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil.
Skaggs School of Pharmacy and Pharmaceutical Sciences. University of California San Diego. La Jolla, California, USA.
Skaggs School of Pharmacy and Pharmaceutical Sciences. University of California San Diego. La Jolla, California, USA.
Università di Salerno. Dipartimento di Farmacia. Salerno, Italy.
Centro Nazionale per il Controllo e la Valutazione dei Farmaci, Istituto Superiore di Sanita. Rome, Italy.
Università degli studi di Firenze. Dipartimento di Chimica. Florence, Italy.
IRBM Science Park. Drug Discovery. Rome, Italy.
IRBM Science Park. Drug Discovery. Rome, Italy.
IRBM Science Park. Drug Discovery. Rome, Italy.
Istituto Pasteur-Fondazione Cenci Bolognetti. Dipartimento di Chimica e Tecnologie del Farmaco. “Sapienza” Università di Roma. Rome, Italy.
Istituto Pasteur-Fondazione Cenci Bolognetti. Dipartimento di Chimica e Tecnologie del Farmaco. “Sapienza” Università di Roma. Rome, Italy.
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 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.
Keywords in Portuguese
Agentes Antiprotozoários
Avaliação biológica
Novos devrivados
 
Keywords
Antiprotozoal Agents
Biological Evaluation
Aril ‑ 1H ‑ pirroli
Fenil
Metil ‑ 1H ‑ imidazole
New derivatives
 
Publisher
American Chemical Society
Citation
SACCOLITI, Francesco et al. Design, Synthesis, and Biological Evaluation of New 1‑(Aryl‑1H‑pyrrolyl)(phenyl)methyl‑1H‑imidazole Derivatives as Antiprotozoal Agents. J. Med. Chem., v. 62, p.1330-1347, 2019.
DOI
10.1021/acs.jmedchem.8b01464
ISSN
0022-2623