Discovery of a Novel Potent Tetrazole Antifungal Candidate with High Selectivity and Broad Spectrum.
J Med Chem
; 67(8): 6238-6252, 2024 Apr 25.
Article
em En
| MEDLINE
| ID: mdl-38598688
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+ 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Tetrazóis
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Candida albicans
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Testes de Sensibilidade Microbiana
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Cryptococcus neoformans
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Antifúngicos
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China