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Sterol 14α-Demethylase Structure-Based Optimization of Drug Candidates for Human Infections with the Protozoan Trypanosomatidae
- Source :
- Journal of Medicinal Chemistry. 61:10910-10921
- Publication Year :
- 2018
- Publisher :
- American Chemical Society (ACS), 2018.
-
Abstract
- Sterol 14α-demethylases (CYP51) are 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 have 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, and is metabolically less stable. In this work we have designed, synthesized, and characterized a set of close analogues 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.
- Subjects :
- Models, Molecular
0301 basic medicine
Chagas disease
Protein Conformation
medicine.drug_class
Trypanosoma cruzi
Antiprotozoal Agents
Article
Microbiology
Sterol 14-Demethylase
03 medical and health sciences
Drug Stability
Microsomes
Drug Discovery
medicine
Humans
Chagas Disease
biology
Chemistry
biology.organism_classification
medicine.disease
Leishmania
Sterol
030104 developmental biology
Visceral leishmaniasis
14-alpha Demethylase Inhibitors
Drug Design
Antiprotozoal
biology.protein
Molecular Medicine
Protozoa
Demethylase
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 61
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....2b5b1cb0c4c1a247385e95bdbfc02850