Abstract：
In previous studies, we developed anti-trypanosome tubulin inhibitors with promising in vitro selectivity and activity against Human African Trypanosomiasis (HAT). However, for such agents, oral activity is crucial. This study focused on further optimizing these compounds to enhance their ligand efficiency, aiming to reduce bulkiness and hydrophobicity, which should improve solubility and, consequently, oral bioavailability. Using Trypanosoma brucei brucei cells as the parasite model and human normal kidney cells and mouse macrophage cells as the host model, we evaluated 30 new analogs synthesized through combinatorial chemistry. These analogs have fewer aromatic moieties and lower molecular weights than their predecessors. Several new analogs demonstrated IC50s in the low micromolar range, effectively inhibiting trypanosome cell growth without harming mammalian cells at the same concentration. We conducted a detailed structure-activity relationship (SAR) analysis and a docking study to assess the compounds\' binding affinity to trypanosome tubulin homolog. The results revealed a correlation between binding energy and anti-Trypanosoma activity. Importantly, compound 7 displayed significant oral activity, effectively inhibiting trypanosome cell proliferation in mice.
摘要：
在以往的研究中,我们开发了抗锥虫微管蛋白抑制剂，具有对人类非洲锥虫病（HAT）的体外选择性和活性。然而,对于这样的特工来说，口腔活动至关重要。这项研究的重点是进一步优化这些化合物，以提高其配体效率，旨在减少体积和疏水性，这应该提高溶解度，因此,口服生物利用度。以布氏锥虫细胞为寄生虫模型，人正常肾细胞和小鼠巨噬细胞为宿主模型，我们评估了通过组合化学合成的30种新类似物。这些类似物具有比其前身更少的芳族部分和更低的分子量。几种新的类似物在低微摩尔范围内显示IC50，有效抑制锥虫细胞生长而不伤害哺乳动物细胞在相同浓度。我们进行了详细的结构-活性关系（SAR）分析和对接研究，以评估化合物与锥虫微管蛋白同源物的结合亲和力。结果表明，结合能与抗锥虫活性之间存在相关性。重要的是,化合物7显示出显着的口服活性，有效抑制小鼠锥虫细胞增殖。
