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Discovery of Novel α,β-Unsaturated Amide Derivatives as Candidate Antifungals to Overcome Fungal Resistance.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2024 Aug 08; Vol. 67 (15), pp. 12601-12617. Date of Electronic Publication: 2024 Jul 30. - Publication Year :
- 2024
-
Abstract
- In our previous study, coumarin-containing CYP51 inhibitor A32 demonstrated potent antiresistance activity. However, compound A32 demonstrated unsatisfied metabolic stability, necessitating modifications to overcome these limitations. In this study, α,β-unsaturated amides were used to replace the unstable coumarin ring, which increased metabolic stability by four times while maintaining antifungal activity, including activity against resistant strains. Subsequently, the sterol composition analysis and morphological observation experiments indicated that the target of these novel compounds is lanosterol 14α-demethylase (CYP51). Meanwhile, biofilm growth was inhibited and resistance genes ( ERG11 , CDR1 , CDR2 , and MDR1 ) expression was downregulated to find out how the antiresistance works. Importantly, compound C07 demonstrated the capacity to stimulate reactive oxygen species, thus displaying potent fungicidal activity. Moreover, C07 exhibited encouraging effectiveness in vivo following intraperitoneal administration. Additionally, the most potent compound C07 showed satisfactory pharmacokinetic properties and low toxicity. These α,β-unsaturated amide derivatives, particularly C07 , are potential candidates for treating azole-resistant candidiasis.
- Subjects :
- Animals
Biofilms drug effects
Candida albicans drug effects
Sterol 14-Demethylase metabolism
Sterol 14-Demethylase chemistry
Mice
Drug Discovery
Structure-Activity Relationship
Coumarins pharmacology
Coumarins chemistry
Coumarins chemical synthesis
14-alpha Demethylase Inhibitors pharmacology
14-alpha Demethylase Inhibitors chemistry
14-alpha Demethylase Inhibitors chemical synthesis
14-alpha Demethylase Inhibitors therapeutic use
Candidiasis drug therapy
Candidiasis microbiology
Reactive Oxygen Species metabolism
Antifungal Agents pharmacology
Antifungal Agents chemistry
Antifungal Agents chemical synthesis
Drug Resistance, Fungal drug effects
Amides pharmacology
Amides chemistry
Amides chemical synthesis
Microbial Sensitivity Tests
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 67
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 39077891
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.4c00593