2. Academic Validation
  3. Biological evaluation and structure-activity relationships of imidazole-based compounds as antiprotozoal agents

Biological evaluation and structure-activity relationships of imidazole-based compounds as antiprotozoal agents

  • Eur J Med Chem. 2018 Aug 5:156:53-60. doi: 10.1016/j.ejmech.2018.06.063.
Francesco Saccoliti 1,  Valentina Noemi Madia 2,  Valeria Tudino 3,  Alessandro De Leo 4,  Luca Pescatori 5,  Antonella Messore 6,  Daniela De Vita 7,  Luigi Scipione 8,  Reto Brun 9,  Marcel Kaiser 10,  Pascal Mäser 11,  Claudia Magalhaes Calvet 12,  Gareth K Jennings 13,  Larissa M Podust 14,  Roberta Costi 15,  Roberto Di Santo 16
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. Electronic address: francesco.saccoliti@uniroma1.it.
  • 2 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. Electronic address: valentinanoemi.madia@uniroma1.it.
  • 3 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. Electronic address: valeria.tudino@uniroma1.it.
  • 4 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. Electronic address: alessandrodl93@gmail.com.
  • 5 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. Electronic address: luca.pescatori@uniroma1.it.
  • 6 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. Electronic address: antonella.messore@gmail.com.
  • 7 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. Electronic address: daniela.devita@uniroma1.it.
  • 8 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. Electronic address: luigi.scipione@uniroma1.it.
  • 9 Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002, Basel, Switzerland. Electronic address: reto.brun@unibas.ch.
  • 10 Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002, Basel, Switzerland. Electronic address: marcel.kaiser@swisstph.ch.
  • 11 Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002, Basel, Switzerland. Electronic address: pascal.maeser@swisstph.ch.
  • 12 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, 92093, USA; Laboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, RJ, 21040-360, Brazil. Electronic address: claudiacalvet@gmail.com.
  • 13 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, 92093, USA. Electronic address: gjennings@ucsd.edu.
  • 14 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, 92093, USA. Electronic address: lpodust@ucsd.edu.
  • 15 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. Electronic address: roberta.costi@uniroma1.it.
  • 16 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. Electronic address: roberto.disanto@uniroma1.it.
PMID: 30006174 DOI: 10.1016/j.ejmech.2018.06.063
Abstract

We discovered a series of azole Antifungal compounds as effective antiprotozoal agents. They displayed promising inhibitory activities within the micromolar-submicromolar range against P. falciparum, L. donovani, and T. b. rhodesiense. Moreover, most of such compounds showed excellent nanomolar IC50 against T. cruzi, showing also very low cytotoxicity. Discussion of structure-activity relationships and biological data for these compounds are provided against the different parasites. To assess the mechanism of action against T. cruzi we proved that the most potent compounds (3b, 3j-l) inhibited the T. cruzi CYP51. Moreover, the most active derivative 3j dramatically reduced parasitemia in T. cruzi mouse model without acute toxicity.

Keywords

Antifungal; Antileishmanial; Antiplasmodial; Antitrypanosomal; Azole; CYP51; In vivo studies.

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