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-β-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 compound 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) accumulation 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.

疲劳对日常生活和工作产生负面影响，严重或慢性疲劳甚至会导致健康问题。研究表明，5-氨基咪唑-4-羧酰胺-1-β-D-呋喃核糖苷（AICAR）可通过激活AMP活化蛋白激酶（AMPK）发挥抗疲劳作用。在这项研究中，合成了六种在核糖部分的羟基位点具有取代的 AICAR 衍生物，并作为抗疲劳剂进行了评估。在动物模型中，所有衍生物均被证明可有效抵抗疲劳。与空白对照组相比，经最佳化合物ZHM-01处理的小鼠在跑轮试验中的力竭距离延长了8.6倍，在负重游泳试验中的力竭时间延长了5.1倍。ZHM-01治疗还减少了运动期间乳酸（LA）和血尿素氮（BUN）的积累。此外，ZHM-01给药增强了 AMPK 的磷酸化，但不刺激中枢神经系统。此外，ZHM-01在为期 21 天的毒性评估中表现出良好的生物安全性。该研究为开发与疲劳相关的健康问题的治疗方法提供了新的参考。