Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614, Poznań, Poland.
Department of Biochemistry, Medical University of Warsaw, 02-097, Warsaw, Poland.
J Antibiot (Tokyo). 2022 Aug;75(8):445-453. doi: 10.1038/s41429-022-00536-4. Epub 2022 Jun 27.
Natural polyether ionophore salinomycin (Sal) has been widely used in veterinary medicine as an antibiotic effective in the treatment of coccidian protozoa and Gram-positive bacteria. Moreover, chemical modification of the Sal structure has been found to be a promising strategy to generate semisynthetic analogs with biological activity profiles improved relative to those of the native compound. In this context, we synthesized and thoroughly evaluated the antibacterial potential of a library of C1/C20 singly and doubly modified derivatives of C20-epi-salinomycin, that is, analogs of Sal with inversed stereochemistry at the C20 position. Among the synthesized analog structures, the most promising antibacterial active agents were those obtained via regioselective O-acylation of C20-epi-hydroxyl, particularly esters 7, 9, and 11. Such C20 singly modified compounds showed excellent inhibitory activity against planktonic staphylococci, both standard and clinical strains, and revealed potential in preventing the formation of bacterial biofilms. In combination with their non-genotoxic properties, these Sal derivatives represent attractive candidates for further antimicrobial drug development.
天然聚醚离子载体盐霉素（Sal）在兽医领域被广泛用作抗生素，对球虫原生动物和革兰氏阳性菌具有疗效。此外，人们发现对 Sal 结构进行化学修饰是一种很有前途的策略，可以生成具有相对天然化合物改善的生物活性谱的半合成类似物。在这种情况下，我们合成并全面评估了 C20-表-盐霉素的 C1/C20 单取代和双取代衍生物文库的抗菌潜力，即 C20 位立体化学反转的 Sal 类似物。在所合成的类似物结构中，通过 C20-表-羟基的区域选择性 O-酰化获得的最有前途的抗菌活性化合物，特别是酯 7、9 和 11。这些 C20 单取代化合物对浮游状态的葡萄球菌，包括标准株和临床株，表现出优异的抑制活性，并显示出预防细菌生物膜形成的潜力。鉴于它们不具有遗传毒性，这些 Sal 衍生物代表了进一步开发抗菌药物的有吸引力的候选物。
