Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, China.
Arch Pharm (Weinheim). 2022 Dec;355(12):e2200266. doi: 10.1002/ardp.202200266. Epub 2022 Aug 27.
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.
侵袭性真菌感染正在成为全球范围内严重的传染病。由于耐药性的频繁出现，侵袭性真菌感染的治疗往往难以实现。分子伴侣 Hsp90 提供了一个有前途的靶点，因为它支持多种病原体的存活、毒力和耐药性。在此，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。作为一种新型真菌 Hsp90 抑制剂，化合物 B25 被发现与氟康唑具有良好的协同作用，并且可以避免潜在的哺乳动物毒性。它在体外也表现出显著的代谢稳定性。总之，B25 可能是一种有前途的针对真菌 Hsp90 的药物发现的先导化合物，值得进一步研究。
