Crotamiton derivative JM03 extends lifespan and improves oxidative and hypertonic stress resistance in <i>Caenorhabditis elegans</i> via inhibiting OSM-9.

Abstract

While screening our in-house 1072 marketed drugs for their ability to extend the lifespan using <i>Caenorhabditis elegans</i> (<i>C. elegans</i>) as an animal model, crotamiton (<i>N</i>-ethyl-o-crotonotoluidide) showed anti-aging activity and was selected for further structural optimization. After replacing the ortho-methyl of crotamiton with ortho-fluoro, crotamiton derivative JM03 was obtained and showed better activity in terms of lifespan-extension and stress resistance than crotamiton. It was further explored that JM03 extended the lifespan of <i>C. elegans</i> through osmotic avoidance abnormal-9 (OSM-9). Besides, JM03 improves the ability of nematode to resist oxidative stress and hypertonic stress through OSM-9, but not osm-9/capsaicin receptor related-2 (OCR-2). Then the inhibition of OSM-9 by JM03 reduces the aggregation of Q35 in <i>C. elegans</i> via upregulating the genes associated with proteostasis. SKN-1 signaling was also found to be activated after JM03 treatment, which might contribute to proteostasis, stress resistance and lifespan extension. In summary, this study explored a new small molecule derived from crotamiton, which has efficient anti-oxidative, anti-hypertonic, and anti-aging effects, and could further lead to promising application prospects.