Skaggs School of Pharmacy and Pharmaceutical Sciences, Center for Discovery and Innovation in Parasitic Diseases, University of California San Diego, La Jolla, California 92093, United States.
Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, p.le Aldo Moro 5, Rome I-00185, Italy.
J Med Chem. 2023 Dec 28;66(24):17059-17073. doi: 10.1021/acs.jmedchem.3c01898. Epub 2023 Dec 12.
Developing drugs for brain infection by is an unmet medical need. We used a combination of cheminformatics, target-, and phenotypic-based drug discovery methods to identify inhibitors that target an essential enzyme, sterol 14-demethylase (NfCYP51). A total of 124 compounds preselected were tested against . Nine primary hits with EC ≤ 10 μM were phenotypically identified. Cocrystallization with NfCYP51 focused attention on one primary hit, miconazole-like compound . The -enantiomer of produced a 1.74 Å cocrystal structure. A set of analogues was then synthesized and evaluated to confirm the superiority of the -configuration over the -configuration and the advantage of an ether linkage over an ester linkage. The two compounds, - and -, had an improved EC and compared to . Importantly, both were readily taken up into the brain. The brain-to-plasma distribution coefficient of - was 1.02 ± 0.12, suggesting further evaluation as a lead for primary amoebic meningoencephalitis.
通过开发针对脑部感染的药物是未满足的医疗需求。我们采用了组合化学、靶标和表型药物发现方法，来鉴定针对关键酶固醇 14α-脱甲基酶（NfCYP51）的抑制剂。总共预筛选了 124 种化合物，并对其进行了测试。9 种 EC 值≤10μM 的主要命中物在表型上被鉴定出来。与 NfCYP51 的共结晶使人们关注到一种主要命中物，咪康唑类似物。化合物 的 -对映异构体产生了 1.74Å 的共晶结构。然后合成了一组类似物，并对其进行了评估，以确认 -构型优于 -构型，以及醚键优于酯键的优势。两种化合物 - 和 - 的 EC 值和 都优于 。重要的是，两者都很容易进入大脑。化合物 - 的脑-血浆分布系数为 1.02±0.12，表明它可进一步作为原发性阿米巴脑膜脑炎的先导化合物进行评估。
