Design, Synthesis, and Activity Evaluation of C-23-Modified 5-<i>O</i>-Mycaminosyltylonolide Derivatives

The widespread use of tylosin family drugs in clinical practice has led to bacterial resistance and reduced therapeutic efficacy. We designed and synthesized a series of new semisynthetic derivatives of tylosin with 5-<i>O</i>-mycaminosyltylonolide as the mother nucleus, mainly by introducing a variety of amino groups at its C-23 position. Some of the compounds showed high antibacterial activity against Gram-negative and Gram-positive bacteria. These findings indicate that the best compound, <b>c9</b>, possessed significant antibacterial activity (MIC = 0.5 ug/mL), excellent bactericidal efficacy, and a low induction rate of drug resistance against <i>Staphylococcus aureus</i> and <i>Escherichia coli</i>; it also showed good antibacterial activity against drug-resistant bacteria. In addition, compound <b>c9</b> has a low toxicity in vitro and in vivo. In conclusion, compound <b>c9</b> could be a potential antimicrobial lead compound that could also contribute to the development of macrolide antibiotics.