In vitro screening of 2-(1H-imidazol-1-yl)-1-phenylethanol derivatives as antiprotozoal agents and docking studies on Trypanosoma cruzi CYP51

Daniela De Vita; Francesca Moraca; Claudio Zamperini; Fabiana Pandolfi; Roberto Di Santo; An Matheeussen; Louis Maes; Silvano Tortorella; Luigi Scipione

doi:10.1016/j.ejmech.2016.02.028

In vitro screening of 2-(1H-imidazol-1-yl)-1-phenylethanol derivatives as antiprotozoal agents and docking studies on Trypanosoma cruzi CYP51

Eur J Med Chem. 2016 May 4:113:28-33. doi: 10.1016/j.ejmech.2016.02.028. Epub 2016 Feb 15.

Authors

Daniela De Vita¹, Francesca Moraca², Claudio Zamperini², Fabiana Pandolfi³, Roberto Di Santo⁴, An Matheeussen⁵, Louis Maes⁵, Silvano Tortorella³, Luigi Scipione³

Affiliations

¹ Department of "Chimica e Tecnologie del Farmaco", Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185 Rome, Italy. Electronic address: daniela.devita@uniroma1.it.
² Department of "Biotecnologie, Chimica e Farmacia", "University of Siena", Via A. Moro 2, 53100 Siena, Italy.
³ Department of "Chimica e Tecnologie del Farmaco", Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185 Rome, Italy.
⁴ Department of "Chimica e Tecnologie del Farmaco", Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185 Rome, Italy; "Istituto Pasteur-Fondazione Cenci Bolognetti", Department of "Chimica e Tecnologie del Farmaco", Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185 Rome, Italy.
⁵ Laboratory for Microbiology, Parasitology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Antwerp University, 2610 Antwerp, Belgium.

PMID: 26922226
DOI: 10.1016/j.ejmech.2016.02.028

Abstract

Sterol 14α-demethylase (CYP51) is a key enzyme involved in the survival and virulence of many parasite protozoa, such as Trypanosoma and Leishmania species, thus representing a valuable drug target for the treatment of Kinetoplastid diseases. A set of azole-based compounds selected from an in-house compound library was in vitro screened against different human protozoan parasites. Several compounds showed selective activity against Trypanosoma cruzi, with compound 7 being the most active (IC50 = 40 nM). Given the structural similarity between the compounds here reported and known CYP51 inhibitors, a molecular docking study was performed to assess their binding with protozoal target and to rationalize the biological activity data.

Keywords: Azoles; CYP51; Trypanosoma cruzi.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiprotozoal Agents / chemical synthesis
Antiprotozoal Agents / chemistry
Antiprotozoal Agents / pharmacology*
Cell Line
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Fibroblasts / drug effects
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry
Imidazoles / pharmacology*
Molecular Docking Simulation
Molecular Structure
Parasitic Sensitivity Tests
Phenylethyl Alcohol / analogs & derivatives*
Phenylethyl Alcohol / chemical synthesis
Phenylethyl Alcohol / chemistry
Phenylethyl Alcohol / pharmacology
Structure-Activity Relationship
Trypanosoma cruzi / drug effects*

Substances

2-(1H-imidazol-1-yl)-1-phenylethanol
Antiprotozoal Agents
Imidazoles
Phenylethyl Alcohol