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

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

  • J Med Chem. 2019 Feb 14;62(3):1330-1347. doi: 10.1021/acs.jmedchem.8b01464.
Francesco Saccoliti 1,  Valentina Noemi Madia 1,  Valeria Tudino 1,  Alessandro De Leo 1,  Luca Pescatori 1,  Antonella Messore 1,  Daniela De Vita 1,  Luigi Scipione 1,  Reto Brun 2,  Marcel Kaiser 2,  Pascal Mäser 2,  Claudia M Calvet 3 4,  Gareth K Jennings 3,  Larissa M Podust 3,  Giacomo Pepe 5,  Roberto Cirilli 6,  Cristina Faggi 7,  Annalise Di Marco 8,  Maria Rosaria Battista 8,  Vincenzo Summa 8,  Roberta Costi 1,  Roberto Di Santo 1
Affiliations

Affiliations

  • 1 Istituto Pasteur-Fondazione Cenci Bolognetti , Dipartimento di Chimica e Tecnologie del Farmaco, "Sapienza" Università di Roma , p. le Aldo Moro 5 , I-00185 Rome , Italy.
  • 2 Swiss Tropical and Public Health Institute , Socinstrasse 57 , CH-4002 Basel , Switzerland.
  • 3 Skaggs School of Pharmacy and Pharmaceutical Sciences , University of California San Diego , La Jolla , California 92093 , United States.
  • 4 Laboratório de Ultraestrutura Celular , Instituto Oswaldo Cruz (IOC), FIOCRUZ, Rio de Janeiro , Rio de Janeiro 21040-360 , Brazil.
  • 5 Dipartimento di Farmacia , Università di Salerno , Via Giovanni Paolo II 132 , I-84084 Fisciano , Salerno , Italy.
  • 6 Centro Nazionale per il Controllo e la Valutazione dei Farmaci , Istituto Superiore di Sanita , Viale Regina Elena 299 , I-00161 Rome , Italy.
  • 7 Dipartimento di Chimica , Università degli studi di Firenze , Via della Lastruccia 13 , I-50019 , Sesto Fiorentino , Florence , Italy.
  • 8 Drug Discovery , IRBM Science Park , Via Pontina km 30,600 , Pomezia, Rome 00071 , Italy.
PMID: 30615444 DOI: 10.1021/acs.jmedchem.8b01464
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.

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