Winter Christian, Siepe Isabella, Wise Andrew, Dorali Alain, Barrett Anthony G M, Witschel Matthias
BASF-SE, D-67056 Ludwigshafen, Germany.
BASF-SE, D-67117 Limburgerhof, Germany.
ACS Med Chem Lett. 2023 Jan 25;14(2):136-140. doi: 10.1021/acsmedchemlett.2c00497. eCollection 2023 Feb 9.
Analysis of the history of the invention of the block-buster antifungal drug Fluconazole underscores the importance of agrochemical research on drug discovery and development. The multidrug resistant fungal pathogen is now responsible for serious morbidity and mortality among immuno-compromised and long-term resident hospital patients globally. New drugs against are urgently needed. A focused screening of 1487 fungicides from the BASF agrochemical collection gave several potent inhibitors of with yet noncommercialized modes of action. The hits showed only minor activity loss against the azole-resistant strain CDC 0385 and low to moderate cytotoxicity to human HepG2 cells. Aminopyrimidine showed high activity against resistant strains and selectivity in a HepG2 cells assay and is a potential hit candidate for further optimization.
对抗真菌重磅药物氟康唑发明历史的分析凸显了农用化学品研究在药物发现与开发中的重要性。多重耐药真菌病原体目前在全球免疫功能低下和长期住院患者中导致严重的发病和死亡。迫切需要针对该病原体的新药。对巴斯夫农用化学品库中的1487种杀菌剂进行的重点筛选得到了几种具有尚未商业化作用模式的强效该病原体抑制剂。这些命中化合物对唑类耐药菌株CDC 0385仅表现出轻微的活性损失，对人肝癌细胞HepG2的细胞毒性低至中等。氨基嘧啶在HepG2细胞试验中对耐药菌株表现出高活性和选择性，是进一步优化的潜在命中候选物。
