福氏痣菌
细胞毒性
效力
体外
IC50型
EC50型
药品
药理学
化学
苄胺
微生物学
脑膜脑炎
生物
生物化学
病毒学
药物化学
作者
Julia M. Pomeroy,Muhammad M. Khalifa,Jillian E. Milanes,Caroline M. Palmentiero,James C. Morris,Jennifer E. Golden
标识
DOI:10.1021/acsmedchemlett.3c00440
摘要
Current therapy for primary amoebic meningoencephalitis (PAM), a highly lethal brain infection in humans caused by Naegleria fowleri amoeba, is restricted to repurposed drugs with limited efficacy and success. Discovery of an antiamoebic benzylamine scaffold 2 precipitated a medicinal chemistry effort to improve potency, cytotoxicity profile, and drug-like properties. Thirty-four compounds were prepared, leading to compound 28 with significant gains in potency (EC50 = 0.92 μM), solubility, and microsomal stability and a demonstrated absence of cytotoxicity in SH-SY5Y human neuroblastoma cells (CC50 > 20 μM). The compounds demonstrated excellent blood–brain barrier permeability in an in vitro assay, thereby providing a new structural scaffold that inhibits N. fowleri viability and permits the investigation of therapeutic interventions in an understudied neglected disease.
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