Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States.
Eukaryotic Pathogens Innovation Center, Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina 29634, United States.
J Med Chem. 2024 Oct 24;67(20):18265-18289. doi: 10.1021/acs.jmedchem.4c01630. Epub 2024 Oct 15.
Primary amoebic meningoencephalitis (PAM) is a human brain infection caused by with a 97% mortality rate. Quinazolinones resulting from a Mannich-coupled domino rearrangement were recently identified as inhibitors of the amoeba. Herein, we resolved the effective concentrations for 25 pilot compounds and then, using the Mannich protocol and a key late-stage, -demethylation/functionalization, we synthesized 53 additional analogs to improve potency, solubility and microsomal stability. We established an antiamoebic quinazolinone pharmacophore, culminating in (±)-- which featured the best combination of potency, selectivity index, solubility, and microsomal stability. Enantiomeric separation afforded (4a,13b)- () with a 41-fold potency advantage over its enantiomer. ADME and mouse pharmacokinetic profiling for revealed high brain penetrance but a limited half-life which did not statistically enhance the mouse survival in a pilot efficacy study. The pharmacophoric model, supported by 88 quinazolinones, several of which exhibit subnanomolar potency, will guide further scaffold optimization.
原发性阿米巴脑膜脑炎（PAM）是一种由 引起的人类脑部感染，其死亡率为 97%。最近发现，Mannich 偶联的多米诺 rearrangement 产生的喹唑啉酮类化合物是变形虫的抑制剂。在此，我们确定了 25 个先导化合物的有效浓度，然后使用 Mannich 方案和关键的晚期脱甲基/功能化，我们合成了 53 个额外的类似物，以提高效力、溶解度和微粒体稳定性。我们建立了一种抗阿米巴喹唑啉酮药效团，最终得到（±）--，其具有最佳的效力、选择性指数、溶解度和微粒体稳定性结合。对映体分离得到（4a,13b）-（），其对映体的效力优势为 41 倍。ADME 和小鼠药代动力学研究表明， 具有高脑穿透性，但半衰期有限，在一项初步疗效研究中并未显著提高小鼠的存活率。该药效团模型得到了 88 个喹唑啉酮的支持，其中一些具有亚纳摩尔的效力，将指导进一步的支架优化。
