Design and Synthesis of a Class of Compounds That Inhibit the Growth of Fungi Which Cause Invasive Infections,ChemistrySelect

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Design and Synthesis of a Class of Compounds That Inhibit the Growth of Fungi Which Cause Invasive Infections
ChemistrySelect ( IF 1.9 ) Pub Date : 2020-01-20 , DOI: 10.1002/slct.201904380
Nana Nakada‐Motokawa _{1,

2} , Taiga Miyazaki _{1,

3} , Satoshi Mizuta ₄ , Yoshimasa Tanaka ₅ , Tatsuro Hirayama ₁ , Takahiro Takazono _{1,

3} , Tomomi Saijo ₁ , Kazuko Yamamoto ₁ , Yoshifumi Imamura ₁ , Koichi Izumikawa ₃ , Katsunori Yanagihara ₆ , Koichi Makimura ₇ , Kohsuke Takeda ₈ , Shigeru Kohno ₁ , Hiroshi Mukae _{1,

2}

Affiliation

Invasive fungal infections are growing causes of morbidity and mortality in immunocompromised patients. However, only one antifungal drug class has been developed in the last 30 years, extremely limiting current therapeutic options. To address unmet medical needs, we performed high‐throughput screening of 9600 chemical compounds and identified an aminohydrazone derivative as a novel and potent antifungal compound. We then designed and synthesized a series of aminohydrazone derivatives, and demonstrated that 1‐[(E)‐[4‐(3′,4′‐dichlorobenxyloxy)phenyl methylidene]amino]‐guanidine had the most potent inhibitory activity and exhibited a broad spectrum of antifungal activities against Candida species (including multidrug resistant C. auris), Aspergillus species, Cryptococcus neoformans, and Rhizopus oryzae. Against C. albicans, the leading cause of Candida infections, the compound had fungicidal activity for planktonic cells at 8 μg mL⁻¹ (25 μM) and anti‐biofilm activity at 34 μg mL⁻¹ (100 μM). This study provides new insights for the development of a new drug class for the treatment of invasive fungal infections which are often refractory to conventional therapies.

中文翻译：

一类抑制引起侵染性真菌生长的化合物的设计与合成

侵袭性真菌感染是免疫功能低下患者发病和死亡的日益严重的原因。然而，在过去的30年中，仅开发了一种抗真菌药物，极大地限制了当前的治疗选择。为了满足未满足的医疗需求，我们对9600种化合物进行了高通量筛选，并确定了氨基hydr衍生物是一种新型且有效的抗真菌化合物。然后，我们设计并合成了一系列氨基hydr衍生物，并证明了1-[（（E）-[4-（3'，4'-二氯苯甲氧基）苯基亚甲基]氨基]-胍具有最强的抑制活性并表现出广泛的抑制作用。念珠菌（包括多药耐药的梭菌）的抗真菌活性谱，曲霉菌种，新型隐球菌和米根霉。针对白色念珠菌，的主要原因念珠菌感染，该化合物具有对浮游细胞的杀真菌活性在8微克毫升^-1（25μM）和抗生物膜活性的34微克毫升^-1（100μM）。这项研究为开发治疗侵入性真菌感染的新药物类别提供了新的见识，这些药物通常对传统疗法是难治的。

更新日期：2020-01-21

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