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

Saccoliti, Francesco and Madia, Valentina Noemi and Tudino, Valeria and De Leo, Alessandro and Pescatori, Luca and Messore, Antonella and De Vita, Daniela and Scipione, Luigi and Brun, Reto and Kaiser, Marcel and Mäser, Pascal and Calvet Alvarez, Claudia Magalhaes and Jennings, Gareth K. and Podust, Larissa M. and Pepe, Giacomo and Cirilli, Roberto and Faggi, Cristina and Di Marco, Annalise and Battista, Maria Rosaria and Summa, Vincenzo and Costi, Roberta and Di Santo, Roberto. (2019) Design, synthesis, and biological evaluation of new 1-(Aryl-1H-pyrrolyl)(phenyl)methyl-1H-imidazole derivatives as antiprotozoal agents. Journal of Medicinal Chemistry, 62 (3). pp. 1330-1347.

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Official URL: https://edoc.unibas.ch/69734/

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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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Brun, Reto and Kaiser, Marcel and Mäser, Pascal
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Chemical Society
ISSN:0022-2623
e-ISSN:1520-4804
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:12 Mar 2019 10:11
Deposited On:12 Mar 2019 10:11

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