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 Caenorhabditis elegans. 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, JX10 exhibited minimal antibacterial activity
and competent antiaging effects in C. elegans, senescent cells, and aged mice. In terms of its mechanism, JX10 acted as a senomorphic agent by suppressing the expression
of p38 MAPK and NF-κB. Furthermore, JX10 demonstrated
favorable safety and pharmacokinetic properties, supporting the feasibility
of JX10 as a promising candidate with the potential for
therapeutic interventions in aging and aging-related diseases.