Design, Synthesis, and Biological Evaluation of New 1-(Aryl-1 H-pyrrolyl)(phenyl)methyl-1 H-imidazole Derivatives as Antiprotozoal Agents

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...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2019-02, Vol.62 (3), p.1330-1347
Main Authors: 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
Format: Article
Language:English
Subjects:
Animals
Antiprotozoal Agents - chemical synthesis
Antiprotozoal Agents - chemistry
Antiprotozoal Agents - pharmacology
Cytochrome P-450 Enzyme Inhibitors - pharmacology
Drug Design
Drug Evaluation, Preclinical
Humans
Imidazoles - chemical synthesis
Imidazoles - chemistry
Imidazoles - pharmacology
Parasitic Sensitivity Tests
Trypanosoma - drug effects
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 IC 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.8b01464