Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0509 USA.
Department of Molecular Microbiology & Immunology, Oregon Health and Science University, Portland, OR 97239, USA.
Bioorg Med Chem Lett. 2024 Dec 1;114:130003. doi: 10.1016/j.bmcl.2024.130003. Epub 2024 Oct 29.
Herein we report a series of antileishmanial analogues derived from 4-[(3,5-dimethyl-4-isoxazolyl)acetyl]-9-[(1-methyl-3-piperidinyl)methoxy]-7-(5-methyl-2-thienyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (1), which was identified through a previously reported high-throughput phenotypic screen. The analogue series was designed, synthesized, and evaluated for antileishmanial activity to establish pharmacophore elements and preliminary structure-activity relationships as key steps in validating the series for further optimization. This study led to identification of the early lead compound 46, which exhibited sub-micromolar proliferation inhibitory activity against intra-macrophage L. mexicana amastigotes, modest selectivity towards host macrophages (J774A.1 line), and good aqueous solubility.
在此，我们报告了一系列源自 4-[(3,5-二甲基-4-异恶唑基)乙酰基]-9-[(1-甲基-3-哌啶基)甲氧基]-7-(5-甲基-2-噻吩基)-2,3,4,5-四氢-1,4-苯并恶嗪 (1) 的抗利什曼原虫类似物。1 是通过之前报道的高通量表型筛选鉴定的。为了确定药效团元素和初步的构效关系，对类似物系列进行了设计、合成和抗利什曼原虫活性评估，这是验证该系列进一步优化的关键步骤。这项研究确定了早期先导化合物 46，它对巨噬细胞内的 L. mexicana 无鞭毛体具有亚微摩尔增殖抑制活性，对宿主巨噬细胞（J774A.1 系）具有适度的选择性，并且水溶性良好。
