Discovery of a Novel Potent Tetrazole Antifungal Candidate with High Selectivity and Broad Spectrum.

Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE

Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-

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; 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

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.

0 (Antifungal Agents)
0 (Tetrazoles)
0 (Cytochrome P-450 Enzyme Inhibitors)
9035-51-2 (Cytochrome P-450 Enzyme System)

Date Created: 20240410 Date Completed: 20240425 Latest Revision: 20240425

20240425

10.1021/acs.jmedchem.3c02188

38598688