Highly potent, broadly active antifungal agents for the treatment of invasive fungal infections
| Autor: | Katie B. Freeman, Jeffrey C. Pelletier, Richard W. Scott, Damian G. Weaver, Simon D P Baugh, Allen B. Reitz, Sandeep Thanna, Anna L Chaly |
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| Rok vydání: | 2020 |
| Předmět: |
Antifungal
Standard of care Antifungal Agents medicine.drug_class Clinical Biochemistry Pharmaceutical Science Microbial Sensitivity Tests Pharmacology 01 natural sciences Biochemistry Structure-Activity Relationship Mammalian cell Drug Discovery medicine Cytotoxicity Molecular Biology Guanidine Candida Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry High mortality Host defence 0104 chemical sciences 010404 medicinal & biomolecular chemistry Aspergillus Molecular Medicine Invasive Fungal Infections |
| Zdroj: | Bioorganicmedicinal chemistry letters. 33 |
| ISSN: | 1464-3405 |
| Popis: | Invasive fungal infections have become an important healthcare issue due in large part to high mortality rates under standard of care (SOC) therapies creating an urgent need for new and effective anti-fungal agents. We have developed a series of non-peptide, structurally-constrained analogs of host defence proteins that have distinct advantages over peptides for pharmaceutical uses. Here we report the chemical optimization of bis-guanidine analogs focused on alterations of the central aryl core and the connection of it to the terminal guanidines. This effort resulted in the production of highly potent, broadly active compounds with low mammalian cell cytotoxicity that have comparable or improved antifungal activities over SOC agents. One optimal compound was also found to possess favourable in vitro pharmaceutical and off-target properties suitable for further development. |
| Databáze: | OpenAIRE |
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