Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch, Cape Town 7701, South Africa.
South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry, University of Cape Town, Rondebosch, Cape Town 7701, South Africa.
J Med Chem. 2021 Jul 8;64(13):9444-9457. doi: 10.1021/acs.jmedchem.1c00707. Epub 2021 Jun 17.
Screening of a library of small polar molecules against () led to the identification of a potent benzoheterocyclic oxime carbamate hit series. This series was subjected to medicinal chemistry progression underpinned by structure-activity relationship studies toward identifying a compound for proof-of-concept studies and defining a lead optimization strategy. Carbamate and free oxime frontrunner compounds with good stability in liver microsomes and no hERG channel inhibition liability were identified and evaluated for pharmacokinetic properties. -mediated permeation and metabolism studies revealed that the carbamates were acting as prodrugs. Toward mechanism of action elucidation, selected compounds were tested in biology triage assays to assess their activity against known promiscuous targets. Taken together, these data suggest a novel yet unknown mode of action for these antitubercular hits.
对（）进行小型极性分子文库筛选，鉴定出了一种有效的苯并杂环肟氨基甲酸酯类命中系列。该系列通过结构活性关系研究进行了药物化学研究，旨在确定一种用于概念验证研究的化合物，并确定了一种先导化合物优化策略。鉴定并评估了具有良好肝微粒体稳定性且无 hERG 通道抑制作用的肟前体化合物和游离肟前体化合物的药代动力学特性。（）介导的渗透和代谢研究表明，氨基甲酸酯类化合物是前药。为了阐明作用机制，选择的化合物在生物学分类测定中进行了测试，以评估它们对已知的混杂靶标的活性。综上所述，这些数据表明这些抗结核命中化合物具有一种新颖但未知的作用机制。
