Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/41369

Type
Article
Copyright
Restricted access
Collections
Share

Statistics
Metadata
Show full item record
Article has an altmetric score of 2

STEROL 14α-DEMETHYLASE STRUCTURE-BASED OPTIMIZATION OF DRUG CANDIDATES FOR HUMAN INFECTIONS WITH THE PROTOZOAN TRYPANOSOMATIDAE
Friggeri, Laura et al. | Date Issued: 2018
Author
Friggeri, Laura
Hargrove, Tatiana Y.
Rachakonda, Girish
Blobaum, Anna L.
Fisher, Paxtyn
Oliveira, Gabriel Melo de
Silva, Cristiane França da
Soeiro, Maria de Nazaré C.
Des, W. David
Lindsey, Craig W.
Villalta, Fernando
Guengerich, F. Peter
Lepesheva, Gallina I.
Affilliation
Vanderbilt University Shcool of Medicine. Department of Biochemistry. Nashville, Tennessee, USA.
Vanderbilt University School of Medicine. Department of Biochemistry. Nashville, Tennesse, USA.
Meharry Medical Center. Department of Microbiology, Immunology and Physiology. Nashville, Tennesse, USA.
Vanderbilt Center for Neuroscience Drug Discovery. Franklin, Tennessee, USA.
Meharry Medical College. Department of Microbiology, Immunology and Physiology. Nashville, Tennessee, USA.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inovações em Terapias, Ensino e Bioprodutos. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Meharry Medical College. Department of Microbiology, Immunology and Physiology. Nashville, Tennessee, USA.
Vanderbilt Center for Neuroscience Drug Discovery. Franklin, Tennesse, USA.
Meharry Mediical College. Department of Microbiology, Immunology and Physiology. Nashville, Tennessee, USA.
Vanderbilt University School of Medicine. Nashville, Tennessee, USA.
Vanderbilt University School of Medicine. Nashville, Tennessee, USA / Meharry Medical College. Department of Microbiology, Immunology and Physiology. Nashville, Tennessee, USA.
Abstract
Sterol 14α-demethylases (CYP51) are the cytochrome P450 enzymes essential for sterol biosynthesis in eukaryotes and therapeutic targets for antifungal azoles. Multiple attempts to repurpose antifungals for treatment of human infections with protozoa (Trypanosomatidae) have been undertaken, yet so far none of them revealed sufficient efficacy. VNI and its derivative VFV are two potent experimental inhibitors of Trypanosomatidae CYP51, effective in vivo against Chagas disease, visceral leishmaniasis, and sleeping sickness and currently under consideration as antiprotozoal drug candidates. However, VNI is less potent against Leishmania and drug-resistant strains of Trypanosoma cruzi and VFV, while displaying a broader spectrum of antiprotozoal activity, is metabolically less stable. In this work we designed, synthesized and characterized a set of close analogs and identified two new compounds (7 and 9) that exceed VNI/VFV in their spectra of antiprotozoal activity, microsomal stability, and pharmacokinetics (tissue distribution in particular) and, like VNI/VFV, reveal no acute toxicity.
Keywords in Portuguese
Trypanosmatidae
infecção em humanos
Sterol 14@
 
Keywords
Trypanosomatidae
Human Infections
Sterol14@
 
Publisher
American Chemical Society
Citation
FRIGGERI, Laura et al. Sterol 14@-Demethylase structure-based optmization of drug candidates for human infections with the Protozoan Trypanosomatidae. Journal of Medicinal Chemistry, v. 61, n, 23, p. 10910-20921, Dec. 2018.
DOI
10.1021/acs.jmedchem.8b01671
ISSN
0022-2623