Discovery of Non-antibacterial Enrofloxacin Derivatives with Emerging Antiaging Effects through Drug Repurposing and Secondary Development

Aging induces dysfunction and increases the risk of chronic diseases in the elderly, positioning the development of antiaging drugs to the forefront of research. Drug repurposing offers an efficient strategy for identifying antiaging lead compounds. In this study, we employed phenotypic screening and discovered that enrofloxacin could extend the lifespan in <i>Caenorhabditis elegans</i>. Based on these findings, we conducted rational drug design to eliminate its antibacterial activity while maintaining the lifespan-extending effect, with the goal of developing safe and novel antiaging compounds. Consequently, <b>JX10</b> exhibited minimal antibacterial activity and competent antiaging effects in <i>C. elegans</i>, senescent cells, and aged mice. In terms of its mechanism, <b>JX10</b> acted as a senomorphic agent by suppressing the expression of p38 MAPK and NF-κB. Furthermore, <b>JX10</b> demonstrated favorable safety and pharmacokinetic properties, supporting the feasibility of <b>JX10</b> as a promising candidate with the potential for therapeutic interventions in aging and aging-related diseases.