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Discovery of a Novel Potent Tetrazole Antifungal Candidate with High Selectivity and Broad Spectrum.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2024 Apr 25; Vol. 67 (8), pp. 6238-6252. Date of Electronic Publication: 2024 Apr 10. - Publication Year :
- 2024
-
Abstract
- Thirty-one novel albaconazole derivatives were designed and synthesized based on our previous work. All compounds exhibited potent in vitro antifungal activities against seven pathogenic fungi. Among them, tetrazole compound D2 was the most potent antifungal with MIC values of <0.008, <0.008, and 2 μg/mL against Candida albicans , Cryptococcus neoformans , and Aspergillus fumigatus , respectively, the three most common and critical priority pathogenic fungi. In addition, compound D2 also exhibited potent activity against fluconazole-resistant C. auris isolates. Notably, compound D2 showed a lower inhibitory activity in vitro against human CYP450 enzymes as well as a lower inhibitory effect on the hERG K <superscript>+</superscript> channel, indicating a low risk of drug-drug interactions and QT prolongation. Moreover, with improved pharmacokinetic profiles, compound D2 showed better in vivo efficacy than albaconazole at reducing fungal burden and extending the survival of C. albicans -infected mice. Taken together, compound D2 will be further investigated as a promising candidate.
- Subjects :
- Animals
Humans
Mice
Structure-Activity Relationship
Aspergillus fumigatus drug effects
Drug Discovery
Drug Resistance, Fungal drug effects
Candidiasis drug therapy
Cytochrome P-450 Enzyme Inhibitors pharmacology
Cytochrome P-450 Enzyme Inhibitors chemical synthesis
Cytochrome P-450 Enzyme Inhibitors chemistry
Cytochrome P-450 Enzyme System metabolism
Antifungal Agents pharmacology
Antifungal Agents chemical synthesis
Antifungal Agents chemistry
Antifungal Agents therapeutic use
Tetrazoles pharmacology
Tetrazoles chemistry
Tetrazoles chemical synthesis
Tetrazoles pharmacokinetics
Tetrazoles therapeutic use
Microbial Sensitivity Tests
Candida albicans drug effects
Cryptococcus neoformans drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 67
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38598688
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.3c02188