Synthesis of analogs of the Gwt1 inhibitor manogepix (APX001A) and in vitro evaluation against Cryptococcus spp
| Autor: | Mili Kapoor, Quinlyn A. Soltow, Michael Trzoss, Molly K. Moloney, Jonathan A. Covel, Peter J. Webb, Karen Joy Shaw |
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| Rok vydání: | 2019 |
| Předmět: |
Antifungal
Antifungal Agents Saccharomyces cerevisiae Proteins medicine.drug_class Clinical Biochemistry Cryptococcus Aminopyridines Pharmaceutical Science Microbial Sensitivity Tests 01 natural sciences Biochemistry Article Fungal Proteins Structure-Activity Relationship chemistry.chemical_compound Biosynthesis Drug Discovery medicine Moiety Molecular Biology Cryptococcus neoformans Fungal protein Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Organic Chemistry Isoxazoles Prodrug biology.organism_classification In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry Molecular Medicine |
| Zdroj: | Bioorg Med Chem Lett |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2019.126713 |
| Popis: | Fosmanogepix (APX001) is a first-in-class prodrug molecule that is currently in Phase 2 clinical trials for invasive fungal infections. The active moiety manogepix (APX001A) inhibits the novel fungal protein Gwt1. Gwt1 catalyzes an early step in the GPI anchor biosynthesis pathway. Here we describe the synthesis and evaluation of 292 new and 24 previously described analogs that were synthesized using a series of advanced intermediates to allow for rapid analoging. Several compounds demonstrated significantly (8- to 32-fold) improved antifungal activity against both Cryptococcus neoformans and C. gattii as compared to manogepix. Further in vitro characterization identified three analogs with a similar preliminary safety and in vitro profile to manogepix and superior activity against Cryptococcus spp. |
| Databáze: | OpenAIRE |
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