Voisinet Megan M, Palmentiero Caroline M, McKeon Jillian E M, Roster Colm P, Carlson Haley M, Brzezinski Thomas D, Burton Kaylin M, Morris James C, Mosey R Adam
Department of Chemistry, Lake Superior State University, Sault Sainte Marie, MI 49783, United States.
Eukaryotic Pathogens Innovation Center, Department of Genetics and Biochemistry, Clemson University, Clemson, SC 29634, United States.
Bioorg Med Chem Lett. 2025 Aug 11;129:130363. doi: 10.1016/j.bmcl.2025.130363.
Primary amoebic meningoencephalitis (PAM) is a brain infection caused by the free-living amoebae Naegleria fowleri. There are few viable treatment options for the infection, resulting in a >97 % fatality rate. Small molecules are being increasingly investigated as treatment options for this deadly infection. This work details the discovery of a dihydroquinazoline that was toxic to the amoeba and subsequent structure-activity relationship (SAR) development of compounds with increasingly potent activity, yielding several early lead candidates exhibiting submicromolar activity (EC = 0.62-0.84 μM) and limited cytotoxicity (CC > 10 μM).
原发性阿米巴脑膜脑炎（PAM）是一种由自由生活的阿米巴原虫福氏耐格里阿米巴引起的脑部感染。针对这种感染，几乎没有可行的治疗方案，导致死亡率超过97%。小分子正越来越多地被研究作为这种致命感染的治疗选择。这项工作详细介绍了一种对阿米巴原虫有毒的二氢喹唑啉的发现，以及随后对活性越来越强的化合物进行的构效关系（SAR）研究，产生了几种早期先导候选物，它们表现出亚微摩尔活性（EC = 0.62 - 0.84 μM）且细胞毒性有限（CC > 10 μM）。
