The NAD⁺-dependent deacetylase SIRT1, which is associated with the improvement of metabolic syndromes, such as type 2 diabetes, is a well-known longevity-related gene. Several in vitro and in vivo studies have shown the known protective effects of SIRT1 activators, such as resveratrol and SRT1720, on diabetes- or obesity-induced fatty liver and insulin resistance. Here, we newly synthesized 18 benzoxazole hydrochloride derivatives based on the structure of resveratrol and SRT1720. We performed an in vitro SIRT1 activity assay to identify the strongest SIRT1 activator. The assay confirmed MHY2233 to be the strongest SIRT1 activator (1.5-fold more potent than resveratrol), and docking simulation showed that the binding affinity of MHY2233 was higher than that of resveratrol and SRT1720. To investigate its beneficial effects, db/db mice were orally administered MHY2233 for 1 month, and various metabolic parameters were assessed in the serum and liver tissues. MHY2233 markedly ameliorated insulin signaling without affecting body weight in db/db mice. In particular, the mRNA expression of lipogenic genes, such as acetyl CoA carboxylase, fatty acid synthase, and sterol regulatory element-binding protein, which increased in db/db mice, decreased following oral treatment with MHY2233.

In conclusion, the novel SIRT1 activator MHY2233 reduced lipid accumulation and improved insulin resistance. This finding may contribute toward therapeutic approaches for fatty liver disease and glucose tolerance.

NAD ⁺依赖性脱乙酰基酶SIRT1是与长寿相关的基因，与代谢综合征（例如2型糖尿病）的改善有关。多项体外和体内研究表明，SIRT1激活剂（如白藜芦醇和SRT1720）对糖尿病或肥胖引起的脂肪肝和胰岛素抵抗具有已知的保护作用。在这里，我们根据白藜芦醇和SRT1720的结构新合成了18种苯并恶唑盐酸盐衍生物。我们进行了体外SIRT1活性测定法可鉴定最强的SIRT1激活剂。该测定证实MHY2233是最强的SIRT1激活剂（效力比白藜芦醇高1.5倍），对接模拟显示，MHY2233的结合亲和力高于白藜芦醇和SRT1720。为了研究其有益效果，对db / db小鼠口服MHY2233进行了1个月的口服给药，并评估了血清和肝脏组织中的各种代谢参数。MHY2233可以显着改善胰岛素信号，而不会影响db / db小鼠的体重。特别是，用MHY2233口服治疗后，在db / db小鼠中增加的脂肪生成基因（例如乙酰CoA羧化酶，脂肪酸合酶和固醇调节元件结合蛋白）的mRNA表达下降。

总之，新型SIRT1激活剂MHY2233减少了脂质积聚并改善了胰岛素抵抗。这一发现可能有助于脂肪肝疾病和葡萄糖耐量的治疗方法。