Discovery of Novel 7-Hydroxy-5-oxo-4,5-dihydrothieno[3,2-b]pyridine-6-carboxamide Derivatives with Potent and Selective Antifungal Activity against Cryptococcus Species,Journal of Medicinal Chemistry

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Discovery of Novel 7-Hydroxy-5-oxo-4,5-dihydrothieno[3,2-b]pyridine-6-carboxamide Derivatives with Potent and Selective Antifungal Activity against Cryptococcus Species
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-08-03 , DOI: 10.1021/acs.jmedchem.2c00794
Liping Li ₁ , Hao Wu ₁ , Shuo Zhu ₁ , Zhe Ji ₁ , Xiaochen Chi _{2,

3} , Fei Xie ₂ , Yumeng Hao ₂ , Hui Lu ₁ , Feng Yang ₁ , Lan Yan ₄ , Dazhi Zhang _{1,

2} , Yuanying Jiang ₁ , Tingjunhong Ni ₁

Affiliation

Cryptococcus neoformans and Cryptococcus gattii can cause fatal invasive infections, especially in immunocompromised patients. However, few antifungal drugs are available to help treat cryptococcosis. In this study, by compound library screening, we presented the first report of hit compound P163-0892, which had potent in vitro and in vivo antifungal activity against Cryptococcus spp. In vitro tests showed that P163-0892 was not cytotoxic and had highly selective and strong antifungal activities against Cryptococcus spp. with MIC values less than 1 μg/mL. Synergism of P163-0892 and fluconazole was also observed in vitro. The in vivo antifungal efficacy of P163-0892 was assessed in a wax moth larval fungal infection model, and treatment with 10 mg/kg P163-0892 caused a significant reduction in fungal burden and significant extension of the survival time. Taken together, our data indicate that the hit compound P163-0892 warrants further investigation as a novel anti-Cryptococcus agent.

中文翻译：

发现对隐球菌具有强效和选择性抗真菌活性的新型 7-Hydroxy-5-oxo-4,5-dihydrothieno[3,2-b]pyridine-6-carboxamide 衍生物

新型隐球菌和加特隐球菌可引起致命的侵袭性感染，尤其是在免疫功能低下的患者中。然而，很少有抗真菌药物可用于帮助治疗隐球菌病。在这项研究中，通过化合物库筛选，我们首次报道了命中化合物P163-0892，该化合物在体外和体内对隐球菌属具有有效的抗真菌活性。体外试验表明，P163-0892无细胞毒性，对隐球菌属具有高度选择性和强抗真菌活性。MIC 值小于 1 μg/mL。P163-0892的协同作用并且在体外也观察到了氟康唑。在蜡蛾幼虫真菌感染模型中评估了P163-0892的体内抗真菌功效，用 10 mg/kg P163-0892处理可显着降低真菌负荷并显着延长存活时间。总之，我们的数据表明，作为一种新型抗隐球菌剂，受打击的化合物P163-0892值得进一步研究。

更新日期：2022-08-03

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