Design, synthesis, and evaluation of novel tetrazoles featuring isoxazole moiety as highly selective antifungal agents. 2023

Tingjunhong Ni, and Xiaochen Chi, and Fei Xie, and Liping Li, and Hao Wu, and Yumeng Hao, and Xiaobo Wang, and Dazhi Zhang, and Yuanying Jiang
Department of Pharmacy, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, No.1239 Siping Road, Shanghai, 200092, China.

In an effort to develop novel azole antifungals with potent activity and high selectivity, a series of (2R,3R)-3-((3-substitutied-phenyl-isoxazol-5-yl)methoxy)-2-(2,4-difluorophenyl)-1-(1H-tetrazol-1-yl)butan-2-ol derivatives were designed and synthesized based on our previously work. All compounds exhibited moderate to excellent in vitro antifungal activities against Candida albicans SC5314 and Cryptococcus neoformans H99, but inactive against Aspergillus fumigatus 7544. Among them, the most active compound 10h displayed outstanding antifungal activity against fluconazole-resistant C. albicans 103, C. glabrata 537 and C. auris 922 with MIC values of ≤0.008 μg/mL. In addition, compound 10h was superior to FLC in inhibiting the filamentation of FLC-resistant C. albicans 103. Notably, compound 10h showed no inhibition of human CYP3A4 with IC50 values of >100 μM, low cytotoxicity at 32 μg/mL and low hERG inhibition with IC50 values of 6.22 μM, suggesting a low risk of drug-drug interactions and good safety profiles. Furthermore, compound 10h exhibited excellent PK profiles and showed remarkable in vivo efficacy in a mouse model of C. albicans and C. neoformans infection. Taken together, compound 10h will be further investigated as a promising lead antifungal agent.

UI MeSH Term Description Entries
D007555 Isoxazoles Azoles with an OXYGEN and a NITROGEN next to each other at the 1,2 positions, in contrast to OXAZOLES that have nitrogens at the 1,3 positions. Isoxazole
D008826 Microbial Sensitivity Tests Any tests that demonstrate the relative efficacy of different chemotherapeutic agents against specific microorganisms (i.e., bacteria, fungi, viruses). Bacterial Sensitivity Tests,Drug Sensitivity Assay, Microbial,Minimum Inhibitory Concentration,Antibacterial Susceptibility Breakpoint Determination,Antibiogram,Antimicrobial Susceptibility Breakpoint Determination,Bacterial Sensitivity Test,Breakpoint Determination, Antibacterial Susceptibility,Breakpoint Determination, Antimicrobial Susceptibility,Fungal Drug Sensitivity Tests,Fungus Drug Sensitivity Tests,Sensitivity Test, Bacterial,Sensitivity Tests, Bacterial,Test, Bacterial Sensitivity,Tests, Bacterial Sensitivity,Viral Drug Sensitivity Tests,Virus Drug Sensitivity Tests,Antibiograms,Concentration, Minimum Inhibitory,Concentrations, Minimum Inhibitory,Inhibitory Concentration, Minimum,Inhibitory Concentrations, Minimum,Microbial Sensitivity Test,Minimum Inhibitory Concentrations,Sensitivity Test, Microbial,Sensitivity Tests, Microbial,Test, Microbial Sensitivity,Tests, Microbial Sensitivity
D002176 Candida albicans A unicellular budding fungus which is the principal pathogenic species causing CANDIDIASIS (moniliasis). Candida albicans var. stellatoidea,Candida stellatoidea,Dematium albicans,Monilia albicans,Myceloblastanon albicans,Mycotorula albicans,Parasaccharomyces albicans,Procandida albicans,Procandida stellatoidea,Saccharomyces albicans,Syringospora albicans
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000440 Butanols Isomeric forms and derivatives of butanol (C4H9OH). Alcohols, Butyl,Butanol,Butylhydroxides,Hydroxybutanes,Butyl Alcohols
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000935 Antifungal Agents Substances that destroy fungi by suppressing their ability to grow or reproduce. They differ from FUNGICIDES, INDUSTRIAL because they defend against fungi present in human or animal tissues. Anti-Fungal Agents,Antifungal Agent,Fungicides, Therapeutic,Antibiotics, Antifungal,Therapeutic Fungicides,Agent, Antifungal,Anti Fungal Agents,Antifungal Antibiotics
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D013777 Tetrazoles
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus

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