Synthetic Derivatives of Ciclopirox are Effective Inhibitors of Cryptococcus neoformans.
Synthetic Derivatives of Ciclopirox are Effective Inhibitors of Cryptococcus neoformans.
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DOI：
10.1021/acsomega.1c00273
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发表时间：
2021-03-30
期刊：
影响因子：
4.1
通讯作者：
Donlin MJ
中科院分区：
文献类型：
--
作者：
Lin J;Zangi M;Kumar TVNH;Shakar Reddy M;Reddy LVR;Sadhukhan SK;Bradley DP;Moreira-Walsh B;Edwards TC;O'Dea AT;Tavis JE;Meyers MJ;Donlin MJ
由新型隐球菌引起的机会性真菌感染是免疫功能低下患者死亡的重要来源。由于抗真菌药物数量有限，治疗它们具有挑战性，因此需要新颖且更有效的抗隐球菌疗法。环吡酮乙醇胺是一种 N-羟基吡啶酮，二十多年来一直被用作治疗局部真菌感染的批准治疗剂。它是一种杀菌剂，对多种真菌具有广泛的活性。我们合成了 10 种 N-羟基吡啶酮衍生物，以初步了解与功效相关的结构-活性，作为开发全身抗真菌药物的起点。我们筛选了衍生物对新型念珠菌和格特隐球菌的抗真菌活性，并反筛选了对白色念珠菌和两种马拉色菌的特异性。十种中的八种在 1-3 μM 浓度（0.17-0.42 μg/mL）下对隐球菌属和白色念珠菌均表现出抑制作用，但对马拉色菌属的活性较差。在新型隐球菌中，N-羟基吡啶酮是杀菌剂，不与氟康唑或两性霉素 B 拮抗，并且与线粒体电子传递链的多种抑制剂具有协同作用。它们似乎主要通过在铁依赖性酶的活性位点内螯合铁来发挥作用。这种初步的结构-活性关系表明，N-羟基吡啶酮环的第六位需要亲脂性官能团，并将第四位和第六位确定为可以耐受进一步取代的位点。这些分子为未来的功效优化和目标识别提供了明确的起点。
Opportunistic fungal infections caused by Cryptococcus neoformans are a significant source of mortality in immunocompromised patients. They are challenging to treat because of a limited number of antifungal drugs, and novel and more effective anticryptococcal therapies are needed. Ciclopirox olamine, a N-hydroxypyridone, has been in use as an approved therapeutic agent for the treatment of topical fungal infections for more than two decades. It is a fungicide, with broad activity across multiple fungal species. We synthesized 10 N-hydroxypyridone derivatives to develop an initial structure–activity understanding relative to efficacy as a starting point for the development of systemic antifungals. We screened the derivatives for antifungal activity against C. neoformans and Cryptococcus gattii and counter-screened for specificity in Candida albicans and two Malassezia species. Eight of the ten show inhibition at 1–3 μM concentration (0.17–0.42 μg per mL) in both Cryptococcus species and in C. albicans, but poor activity in the Malassezia species. In C. neoformans, the N-hydroxypyridones are fungicides, are not antagonistic with either fluconazole or amphotericin B, and are synergistic with multiple inhibitors of the mitochondrial electron transport chain. They appear to function primarily by chelating iron within the active site of iron-dependent enzymes. This preliminary structure–activity relationship points to the need for a lipophilic functional group at position six of the N-hydroxypyridone ring and identifies positions four and six as sites where further substitution may be tolerated. These molecules provide a clear starting point for future optimization for efficacy and target identification.
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影响因子：
64.5
作者：
Liu OW;Chun CD;Chow ED;Chen C;Madhani HD;Noble SM
通讯作者：
Noble SM
影响因子：
64.5
作者：
Brown JCS;Nelson J;VanderSluis B;Deshpande R;Butts A;Kagan S;Polacheck I;Krysan DJ;Myers CL;Madhani HD
通讯作者：
Madhani HD
影响因子：
7.3
作者：
Liu Z;Yao Y;Kogiso M;Zheng B;Deng L;Qiu JJ;Dong S;Lv H;Gallo JM;Li XN;Song Y
通讯作者：
Song Y
影响因子：
12.8
作者：
Minden, Mark D.;Hogge, Donna E.;Schimmer, Aaron D.
通讯作者：
Schimmer, Aaron D.
影响因子：
20.3
作者：
Eberhard, Yanina;McDermott, Sean P.;Schimmer, Aaron D.
通讯作者：
Schimmer, Aaron D.