Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Department of Pathology & Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Molecules. 2022 Feb 24;27(5):1518. doi: 10.3390/molecules27051518.
Infections due to Gram-negative bacteria are increasingly dangerous due to the spread of multi-drug resistant strains, emphasizing the urgent need for new antibiotics with alternative modes of action. We have previously identified a novel class of antibacterial agents, thioacetamide-triazoles, using an antifolate targeted screen and determined their mode of action which is dependent on activation by cysteine synthase A. Herein, we report a detailed examination of the anti- structure-activity relationship of the thioacetamide-triazoles. Analogs of the initial hit compounds were synthesized to study the contribution of the aryl, thioacetamide, and triazole sections. A clear structure-activity relationship was observed generating compounds with excellent inhibition values. Substitutions to the aryl ring were generally best tolerated, including the introduction of thiazole and pyridine heteroaryl systems. Substitutions to the central thioacetamide linker section were more nuanced; the introduction of a methyl branch to the thioacetamide linker substantially decreased antibacterial activity, but the isomeric propionamide and -benzamide systems retained activity. Changes to the triazole portion of the molecule dramatically decreased the antibacterial activity, further indicating that 1,2,3-triazole is critical for potency. From these studies, we have identified new lead compounds with desirable in-vitro ADME properties and in-vivo pharmacokinetic properties.
由于多药耐药菌株的传播，革兰氏阴性菌引起的感染变得越来越危险，这强调了迫切需要具有替代作用模式的新型抗生素。我们之前使用抗叶酸靶向筛选发现了一类新型抗菌剂——硫代乙酰胺-三唑，并确定了其作用模式，该模式依赖于半胱氨酸合酶 A 的激活。在此，我们报告了对硫代乙酰胺-三唑的详细抗结构-活性关系研究。合成了初始命中化合物的类似物，以研究芳基、硫代乙酰胺和三唑部分的贡献。观察到明确的构效关系，生成了具有优异抑制值的化合物。芳基环的取代通常最能耐受，包括噻唑和吡啶杂芳环系统的引入。对于位于中心的硫代乙酰胺连接部分的取代更加微妙；硫代乙酰胺连接部分引入甲基支链会大大降低抗菌活性，但异构体丙酰胺和苯甲酰胺系统仍保持活性。分子中三唑部分的变化会显著降低抗菌活性，进一步表明 1,2,3-三唑对效力至关重要。通过这些研究，我们确定了具有理想的体外 ADME 性质和体内药代动力学性质的新先导化合物。
