Synthesis and in vitro evaluation of chlorogenic acid amides as potential hypoglycemic agents and their synergistic effect with acarbose
Synthesis and in vitro evaluation of chlorogenic acid amides as potential hypoglycemic agents and their synergistic effect with acarbose
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DOI：
10.1016/j.bioorg.2021.105458
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发表时间：
2021-12-01
影响因子：
5.1
通讯作者：
Tringali, Corrado
中科院分区：
文献类型：
--
作者：
Cardullo, Nunzio;Floresta, Giuseppe;Tringali, Corrado
2型糖尿病是一种慢性疾病，被认为是最严重的全球卫生紧急情况之一。绿原酸（1）已被证明可以通过抑制α-葡萄糖苷酶（α-Glu）和α-淀粉酶（α-Amy）的活性来延迟肠道葡萄糖吸收。在本工作中，11个绿原酸酰胺已被合成和评价其抗氧化性能（DPPH中心点和ORAC）和对两种酶的抑制活性，目的是获得双重作用的抗糖尿病药物。两种最有希望的降血糖化合物，在烷基链上带有叔胺官能团（8）和苯并噻唑骨架（11），显示出低于（1）的IC 50值（45.5 μ M α-Glu; 105.2 μ M α-Amy）。酰胺8和11是比抗糖尿病药物阿卡波糖（IC 50 = 268.4 μ M）有效得多的α-Glu抑制剂，并且对α-Amy的活性比阿卡波糖（IC 50 = 34.4 μ M）低约两倍。对酰胺8和11的动力学实验表明，这些化合物是α-Glu的混合型抑制剂，K-i'值分别为13.3和6.3 μ M。淀粉酶抑制作用在8（Ki = 79.7 μ M）存在下以竞争性机制发生，在11（Ki = 19.1 μ M; Ki ' = 93.6 μ M）存在下以混合型机制发生。分子对接分析支持这些结果，突出了额外的结合位点在两种酶的存在。荧光实验证实，酰胺8和11对两种酶的亲和力比（1）高。此外，当加入阿卡波糖和酰胺11进行抑制试验时，观察到阿卡波糖功效的显著增强。上述结果明确指出，苯并噻唑基酰胺11作为单独或与阿卡波糖联合治疗2型糖尿病的进一步研究的有希望的候选物。
Type 2 Diabetes mellitus is a chronic disease considered one of the most severe global health emergencies. Chlorogenic acid (1) has been shown to delay intestinal glucose absorption by inhibiting the activity of alpha-glucosidase (alpha-Glu) and alpha-amylase (alpha-Amy). In the present work, eleven chlorogenic acid amides have been synthesized and evaluated for their antioxidant properties (as DPPH center dot and ORAC) and inhibition activity towards the two enzymes and, with the aim to obtain dual-action antidiabetic agents. The two most promising hypoglycemic compounds, bearing a tertiary amine function on an alkyl chain (8) and a benzothiazole scaffold (11), showed IC50 values lower than that of (1) (45.5 mu M alpha-Glu; 105.2 mu M alpha-Amy). Amides 8 and 11 were by far more potent alpha-Glu inhibitors than the antidiabetic drug acarbose (IC50 = 268.4 mu M) and about twice less active toward alpha-Amy than acarbose (IC50 = 34.4 mu M). Kinetics experiments on amides 8 and 11 indicated these compounds as mixed-type inhibitors of alpha-Glu with K-i' values of 13.3 and 6.3 mu M, respectively. The amylase inhibition occurred with a competitive mechanism in the presence of 8 (K-i = 79.7 mu M) and with a mixed-type mechanism with 11 (K-i = 19.1 mu M; K-i' = 93.6 mu M). Molecular docking analyses supported these results, highlighting the presence of additional binding sites in both enzymes. Fluorescence experiments confirmed the grater affinity of amides 8 and 11 towards the two enzymes respect to (1). Moreover, a significant enhancement in acarbose efficacy was observed when inhibition assays were performed adding acarbose and amide 11. The above outcomes pinpointed the benzothiazole-based amide 11 as a promising candidate for further studies on type 2 diabetes treatment, both alone or combined with acarbose.