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

Francesco Saccoliti; Valentina Noemi Madia; Valeria Tudino; Alessandro De Leo; Luca Pescatori; Antonella Messore; Daniela De Vita; Luigi Scipione; Reto Brun; Marcel Kaiser; Pascal Mäser; Claudia Magalhaes Calvet; Gareth K Jennings; Larissa M Podust; Roberta Costi; Roberto Di Santo

doi:10.1016/j.ejmech.2018.06.063

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. Epub 2018 Jun 28.

Authors

Francesco Saccoliti¹, Valentina Noemi Madia², Valeria Tudino³, Alessandro De Leo⁴, Luca Pescatori⁵, Antonella Messore⁶, Daniela De Vita⁷, Luigi Scipione⁸, Reto Brun⁹, Marcel Kaiser¹⁰, Pascal Mäser¹¹, Claudia Magalhaes Calvet¹², Gareth K Jennings¹³, Larissa M Podust¹⁴, Roberta Costi¹⁵, Roberto Di Santo¹⁶

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.

MeSH terms

Animals
Antiprotozoal Agents / chemical synthesis
Antiprotozoal Agents / chemistry*
Antiprotozoal Agents / pharmacology*
Antiprotozoal Agents / therapeutic use
Cell Line
Chagas Disease / drug therapy*
Female
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry*
Imidazoles / pharmacology*
Imidazoles / therapeutic use
Inhibitory Concentration 50
Leishmania donovani / drug effects
Leishmaniasis, Visceral / drug therapy
Malaria, Falciparum / drug therapy
Mice
Mice, Inbred BALB C
Parasitic Sensitivity Tests
Plasmodium falciparum / drug effects
Rats
Structure-Activity Relationship
Trypanosoma brucei rhodesiense / drug effects
Trypanosoma cruzi / drug effects*
Trypanosomiasis, African / drug therapy

Substances

Antiprotozoal Agents
Imidazoles