Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, Université de Paris, 45, rue des saints-pères, Paris, 75006, France.
INSERM UMRS 1138, Sorbonne Universités, UPMC Univ Paris 06, Sorbonne Paris Cité, Université de Paris, Centre de recherche des Cordeliers, Paris, 75006, France.
Chemistry. 2021 Feb 15;27(10):3542-3551. doi: 10.1002/chem.202004831. Epub 2021 Jan 21.
The carbapenem class of β-lactams has been optimized against Gram-negative bacteria producing extended-spectrum β-lactamases by introducing substituents at position C2. Carbapenems are currently investigated for the treatment of tuberculosis as these drugs are potent covalent inhibitors of l,d-transpeptidases involved in mycobacterial cell wall assembly. The optimization of carbapenems for inactivation of these unusual targets is sought herein by exploiting the nucleophilicity of the C8 hydroxyl group to introduce chemical diversity. As β-lactams are structure analogs of peptidoglycan precursors, the substituents were chosen to increase similarity between the drug and the substrate. Fourteen peptido-carbapenems were efficiently synthesized. They were more effective than the reference drug, meropenem, owing to the positive impact of a phenethylthio substituent introduced at position C2 but the peptidomimetics added at position C8 did not further improve the activity. Thus, position C8 can be modified to modulate the pharmacokinetic properties of highly efficient carbapenems.
碳青霉烯类β-内酰胺类药物通过在 C2 位置引入取代基，针对产生扩展谱β-内酰胺酶的革兰氏阴性细菌进行了优化。由于这些药物是参与分枝杆菌细胞壁组装的 l,d-转肽酶的有效共价抑制剂，因此目前正在研究碳青霉烯类药物治疗结核病。本文通过利用 C8 羟基的亲核性引入化学多样性，寻求对这些不寻常靶标的碳青霉烯类药物的失活进行优化。由于β-内酰胺类药物是肽聚糖前体的结构类似物，因此选择取代基以增加药物与底物之间的相似性。十四种肽碳青霉烯类化合物被有效地合成。由于在 C2 位置引入的苯乙基硫取代基的积极影响，它们比参考药物美罗培南更有效，但在 C8 位置添加的肽模拟物并没有进一步提高活性。因此，C8 位置可以进行修饰，以调节高效碳青霉烯类药物的药代动力学特性。
