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

Abstract

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 4,5diarylisoxazole 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.

Discovery of CZS-241: A Potent, Selective, and Orally Available Polo-Like Kinase 4 Inhibitor for the Treatment of Chronic Myeloid Leukemia

“…The human plasma includes quantities of hydrolases, such as aldolase, cholinesterase, and lipase, which could also metabolize drugs . As a large class of metal-containing enzymes, CYPs are involved in the metabolism of masses of endogenous and exogenous compounds .…”

Design, synthesis, and evaluation of novel 3,4‐isoxazolediamide derivatives for the combination treatment of azole‐resistant candidiasis

“…Among them, the p ‐tolyl moiety at the C‐3 position of resorcinol was retained because it was shown to be effective in achieving species selectivity in humans and fungi as previously reported. [ 26 ] Accordingly, we constructed a series of basic structural motifs of 3,4‐isoxazolediamide analogs. All synthesized compounds were co‐administered to evaluate the in vitro activity of potential fungal Hsp90 inhibitors against six azole‐resistant fungi.…”

“…Compounds B25 and C2 were also tested for their synergistic effects with FLC against azole‐resistant Candida albicans strains, which showed excellent synergistic activities (fractional inhibitory concentration index [FICI] = 0.023−0.047, Table 4). [ 26 ]…”

“…With NVP‐AUY922 (AUY‐922) as the lead compound, compound A17 obtained through multiple rounds of structural modification by the research group can significantly enhance fluconazole (FLC)‐resistant Candida albicans activity and initially achieve species selectivity. [ 26 ] However, its further application is limited by its short half‐life ( T 1/2 = 32.1 min). Subsequently, we performed structural optimization and structure–activity relationship (SAR) studies on A17 to achieve activity against drug‐resistant fungi while also having suitable drug‐like properties.…”

“…With NVP-AUY922 (AUY-922) as the lead compound, compound A17 obtained through multiple rounds of structural modification by the research group can significantly enhance fluconazole (FLC)-resistant Candida albicans activity and initially achieve species selectivity. [26] However, its further application is limited by its short half-life (T 1/2 = 32.1 min).…”