Discovery of 5-Nitro-6-thiocyanatopyrimidines as Inhibitors of Cryptococcus neoformans and Cryptococcus gattii.
Discovery of 5-Nitro-6-thiocyanatopyrimidines as Inhibitors of Cryptococcus neoformans and Cryptococcus gattii.
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发现 5-Nitro-6-thiocyanatopyrimidines 作为新型隐球菌和格特隐球菌的抑制剂。
DOI：
10.1021/acsmedchemlett.1c00038
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发表时间：
2021
影响因子：
4.2
通讯作者：
Ekins,Sean
中科院分区：
文献类型：
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作者：
Donlin,MaureenJ;Lane,ThomasR;Riabova,Olga;Lepioshkin,Alexander;Xu,Evan;Lin,Jeffrey;Makarov,Vadim;Ekins,Sean
致病真菌的机会性感染对医疗保健构成了重大挑战，因为抗真菌药物的武器库非常有限，免疫抑制患者的数量不断增加，以及由于过度使用少数可用的抗真菌药物而导致的耐药临床菌株的流行。隐球菌性脑膜炎是一种危及生命的机会性真菌感染，由隐球菌属的两种之一引起，即新生隐球菌和隐球菌。80%的隐球菌病是由C。在环境中是地方病的新生物。护理标准仅限于老的抗真菌药物，在高标准护理下，死亡率保持在10%至30%之间。我们利用体外和计算机器学习的方法，已经确定了一系列5-硝基-6-硫氰基嘧啶类抗真菌药物的候选化合物。这些化合物可以抑制C。亚微摩尔水平的肿瘤生长对氟康唑耐药C有效。和一株临床分离的Fc。Gattii，与目前批准的抗真菌药物没有拮抗作用。
Opportunistic infections from pathogenic fungi present a major challenge to healthcare because of a very limited arsenal of antifungal drugs, an increasing population of immunosuppressed patients, and increased prevalence of resistant clinical strains due to overuse of the few available antifungals. Cryptococcal meningitis is a life-threatening opportunistic fungal infection caused by one of two species in theCryptococcusgenus,Cryptococcus neoformansandCryptococcus gattii. Eighty percent of cryptococcosis diseases are caused byC. neoformansthat is endemic in the environment. The standard of care is limited to old antifungals, and under a high standard of care, mortality remains between 10 and 30%. We have identified a series of 5-nitro-6-thiocyanatopyrimidine antifungal drug candidates usingin vitroand computational machine learning approaches. These compounds can inhibitC. neoformansgrowth at submicromolar levels, are effective against fluconazole-resistantC. neoformansand a clinical strain ofC. gattii, and are not antagonistic with currently approved antifungals.