Optimization and Evaluation of Novel Antifungal Agents for the Treatment of Fungal Infection
| Autor: | Ye Rim Lee, Kyung-Tae Lee, Dong-Gi Lee, Hyeon Jeong Kim, Eunji Cheong, Jong Hyun Park, Hyeon Ji Kim, Seul Ki Yeon, Yong Sun Bahn, Myung Ha Lee, Jiwon Choi, Da-Hee Kim, Siwon Kim, Kyung Jin Seo, Bo Ko Jang, Sun Jun Park, Jong-Seung Lee, Ki Duk Park |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Antifungal Antifungal Agents Nail Infection medicine.drug_class Antifungal drugs Drug Evaluation Preclinical Microbial Sensitivity Tests Microbiology Rats Sprague-Dawley Mice Cell Wall Drug Discovery medicine Animals Humans Chemistry Fungi Drug Synergism Fungicide Mycoses Cell wall integrity Minimum Inhibitory Concentration Test Molecular Medicine Female Ex vivo |
| Zdroj: | Journal of Medicinal Chemistry. 64:15912-15935 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.1c01299 |
| Popis: | Due to the increased morbidity and mortality by fungal infections and the emergence of severe antifungal resistance, there is an urgent need for new antifungal agents. Here, we screened for antifungal activity in our in-house library through the minimum inhibitory concentration test and derived two hit compounds with moderate antifungal activities. The hit compounds' antifungal activities and drug-like properties were optimized by substituting various aryl ring, alkyl chain, and methyl groups. Among the optimized compounds, 22h was the most promising candidate with good drug-like properties and exhibited potent fast-acting fungicidal antifungal effects against various fungal pathogens and synergistic antifungal activities with some known antifungal drugs. Additionally, 22h was further confirmed to disturb fungal cell wall integrity by activating multiple cell wall integrity pathways. Furthermore, 22h exerted significant antifungal efficacy in both the subcutaneous infection mouse model and ex vivo human nail infection model. |
| Databáze: | OpenAIRE |
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