Synthesis and evaluation of 5-aminimidazole-4-carboxamide riboside derivatives as anti-fatigue agents

Fatigue has a negative influence on daily life and work, and serious or chronic fatigue can even cause health problems. Studies have shown that 5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside (AICAR) can exert anti-fatigue effects by activating AMP-activated protein kinase (AMPK). In this study, six AICAR derivatives with substitution at the hydroxyl sites of the ribose moiety were synthesized and evaluated as anti-fatigue agents. All of the derivatives were demonstrated to effectively resist fatigue in animal models. The mice treated with the optimal com-pound ZHM-01 showed an 8.6-fold greater exhaustion distance in the running wheel test and a 5.1 -fold greater exhaustion time in the weight-loaded swimming test than those of the blank control group. ZHM-01 treatment also reduced lactic acid (LA) and blood urea nitrogen (BUN) accumu-lation during exercise. In addition, ZHM-01 administration enhanced the phosphorylation of AMPK but did not excite the central nervous system. Moreover, ZHM-01 showed good biological safety in a 21-day toxicity evaluation. This study provides a new reference for the development of treatments for fatigue-related health problems. (c) 2022 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).