噻唑烷衍生物的设计、合成、建模研究及生物评价，该类噻唑烷衍生物以吡唑为核心，作为潜在的抗糖尿病 PPAR-γ 激动剂和抗炎 COX-2 选择性抑制剂。
Design, synthesis, modeling studies and biological evaluation of thiazolidine derivatives containing pyrazole core as potential anti-diabetic PPAR-γ agonists and anti-inflammatory COX-2 selective inhibitors.
机构信息
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt; Pharmaceutical Sciences Department, Ibn Sina National College for Medical Studies, Jeddah 21418, Saudi Arabia.
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.
出版信息
Bioorg Chem. 2019 Feb;82:86-99. doi: 10.1016/j.bioorg.2018.09.034. Epub 2018 Sep 25.
Nowadays, diabetes and its associated inflammatory complications are important public health problems worldwide. Market limitations of drugs with dual actions as anti-inflammatory (AI) and anti-diabetic have been led to a temptation for focusing on the discovery and development of new compounds with potential AI and anti-diabetic activities. Herein, we synthesized two new series containing pyrazole ring with vicinal diaryl rings as selective COX-2 moiety and thiazolidindione (series 12a-f) or thiazolidinone (series 13a-f) as anti-diabetic moiety and the two moieties were linked together with methylene or methylenehydrazone functionality. The two series were evaluated for their COX inhibition, AI activity and ulcerogenic liability and for the anti-diabetic activity; 12a-f and 13a-f were assessed in vitro against α-glucosidase, β- glucosidase, in vivo hypoglycemic activity (one day and 15 days studies) in addition to PPARγ activation study. Four compounds (12c, 12f, 13b and 13f) had higher COX-2 S.I. (8.69-9.26) than the COX-2 selective drug celecoxib (COX-2 S.I. = 8.60) and showed the highest AI activities and the lowest ulcerogenicity than other derivatives. Also, two thiazolidindione derivatives 12e and 12f and two thiazolidinone derivatives 13b and 13c showed higher inhibitory activities against α- and β-glucosidase (% inhibitory activity = 62.15, 55.30, 65.37, 59.08 for α-glucosidase and 57.42, 60.07, 58.19, 66.90 for β-glucosidase respectively) than reference compounds (acarbose with % inhibitory activity = 49.50 for α-glucosidase and d-saccharic acid 1,4-lactone monohydrate with % inhibitory activity = 53.42 for β-glucosidase) and also showed good PPAR-γ activation and good hypoglycemic effect in comparison to pioglitazone and rosiglitazone. Moreover, Shape comparison and docking studies were carried out to understand their interaction and similarity with standard drugs.
如今，糖尿病及其相关炎症并发症是全球重要的公共卫生问题。具有抗炎（AI）和抗糖尿病双重作用的药物市场局限性导致人们渴望发现和开发具有潜在 AI 和抗糖尿病活性的新化合物。在这里，我们合成了两个含有吡唑环的新系列，其中包括邻二芳基作为选择性 COX-2 部分和噻唑烷二酮（系列 12a-f）或噻唑烷酮（系列 13a-f）作为抗糖尿病部分，两个部分通过亚甲基或亚甲基腙功能连接在一起。这两个系列的 COX 抑制、AI 活性和致溃疡性进行了评估，并对其抗糖尿病活性进行了评估；12a-f 和 13a-f 在体外针对α-葡萄糖苷酶、β-葡萄糖苷酶进行了评估，在体内进行了 1 天和 15 天的研究，以及 PPARγ 激活研究。四种化合物（12c、12f、13b 和 13f）的 COX-2 SI（8.69-9.26）高于 COX-2 选择性药物塞来昔布（COX-2 SI = 8.60），且 AI 活性最高，致溃疡性最低与其他衍生物相比。此外，两种噻唑烷二酮衍生物 12e 和 12f 以及两种噻唑烷酮衍生物 13b 和 13c 对α-和β-葡萄糖苷酶的抑制活性更高（对α-葡萄糖苷酶的抑制活性分别为 62.15%、55.30%、65.37%、59.08%，对β-葡萄糖苷酶的抑制活性分别为 57.42%、60.07%、58.19%、66.90%）比参考化合物（阿卡波糖对α-葡萄糖苷酶的抑制活性为 49.50%，D-山梨糖醇 1,4-内酯一水合物对β-葡萄糖苷酶的抑制活性为 53.42%），并且与吡格列酮和罗格列酮相比，还具有良好的 PPAR-γ 激活和良好的降血糖作用。此外，进行了形状比较和对接研究，以了解它们与标准药物的相互作用和相似性。
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