Abstract：
Invasive fungal infections are emerging as serious infectious diseases worldwide. Due to the frequent emergence of resistance, the cure for invasive fungal infections is often unachievable. The molecular chaperone Hsp90 provides a promising target because it supports survival, virulence, and drug resistance in a variety of pathogens. Herein, we report on the structural optimization and structure-activity relationship studies of 3,4-isoxazolediamide analogs. As a new class of fungal Hsp90 inhibitor, compound B25 was found to have good synergistic effects with fluconazole and to avoid potential mammalian toxicity. It also showed remarkable metabolic stability in vitro. Collectively, B25 could be a promising lead compound for drug discovery targeting fungal Hsp90 and deserves further investigation.
摘要：
侵袭性真菌感染正在世界范围内成为严重的传染病。由于阻力的频繁出现，侵袭性真菌感染的治愈通常是无法实现的。分子伴侣Hsp90提供了一个有前途的目标，因为它支持生存，毒力,以及多种病原菌的耐药性。在这里，我们报告了3,4-异恶唑二酰胺类似物的结构优化和构效关系研究。作为一类新型的真菌Hsp90抑制剂，发现化合物B25与氟康唑具有良好的协同作用并避免潜在的哺乳动物毒性。它还在体外显示出显著的代谢稳定性。总的来说，B25可能是靶向真菌Hsp90的药物发现的有前途的先导化合物，值得进一步研究。
