Species-Selective Targeting of Fungal Hsp90: Design, Synthesis, and Evaluation of Novel 4,5-Diarylisoxazole Derivatives for the Combination Treatment of Azole-Resistant Candidiasis

Invasive
fungal infections are emerging as serious infectious diseases
worldwide. Because of the development of antifungal drug resistance,
the limited efficacy of the existing drugs has led to high mortality
in patients. The use of the essential eukaryotic chaperone Hsp90,
which plays a multifaceted role in drug resistance across diverse
pathogenic fungal species, is considered to be a new strategy to mitigate
the resistance and counter the threat posed by drug-resistant fungi.
Thus, a series of 4,5-diarylisoxazole analogues as fungal Hsp90 inhibitors
were designed and synthesized that had potent synergistic effects
with fluconazole in vitro and in vivo. In particular, compound A17 could avoid the potential
mammalian toxicity of Hsp90 inhibitors based on key reside differences
between humans and fungi. These data support the feasibility of targeting
fungal Hsp90 as a promising antifungal strategy and further development
of compound A17 as a valuable research probe for the
investigation of fungal Hsp90.