Functionalized quinazolinone derivatives 1–30 were synthesized by two-step reaction. First, anthranilic acid was treated with substituted phenyl isothiocyanate to synthesize 3-aryl-2-thioxo-2,3-dihydroquinazolinone derivatives 1–8 which in turn reacted with different bromoacetophenone derivatives to obtain fully functionalized quinazolinone derivatives 9–30. Both reactions were catalyzed by triethylamine. All the products were characterized by EI-, HREI-MS, ¹H-, and ¹³CNMR spectroscopic techniques. All compounds were subjected to their in vitro α-glucosidase inhibitory activity. Results showed that except compound 1–3, 5, 7, and 22, all compounds were found potent and showed many folds increased α-glucosidase enzyme inhibition as compared to standard acarbose (IC₅₀ = 750.0 ± 10.0 µM). Compound 13 (IC₅₀ = 85.0 ± 0.5 µM) was recognized as the most potent analog of the whole series, with ninefold enhanced inhibitory potential than the standard acarbose. Compounds 1–9, 11, 12, 22, and 26 were structurally known compounds, while remaining all are new. Kinetic study on compound 13 showed that the compound is following a competitive-type inhibition mechanism. Furthermore, in silico studies have also been performed to better rationalize the interactions between synthetic compound and active site of the enzyme.

Graphic abstract

中文翻译：

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新型，功能化的喹唑啉酮类似物的合成，体外和计算机模拟研究，用于鉴定有效的α-葡萄糖苷酶抑制剂

通过两步反应合成了功能化的喹唑啉酮衍生物1-30。首先，用取代的异硫氰酸苯酯处理邻氨基苯甲酸，合成3-芳基-2-硫代-2,3-二氢喹唑啉酮衍生物1–8，然后与不同的溴苯乙酮衍生物反应，得到功能完全的喹唑啉酮衍生物9–30。两种反应均由三乙胺催化。所有产品均通过EI-，HREI-MS，¹ H-和¹³ CNMR光谱技术进行了表征。所有化合物均具有体外α-葡萄糖苷酶抑制活性。结果表明，除化合物1-3，5，如图7和22所示，与标准阿卡波糖（IC ₅₀  = 750.0±10.0 µM）相比，发现所有化合物均有效，并且对α-葡萄糖苷酶的抑制作用提高了许多倍。化合物13（IC ₅₀  = 85.0±0.5 µM）被认为是整个系列中最有效的类似物，其抑制潜力是标准阿卡波糖的九倍。化合物1-9，11，12，22，和26在结构上的已知化合物，而其余所有都是新的。化合物13的动力学研究表明该化合物遵循竞争性抑制机制。此外，还进行了计算机模拟研究，以更好地合理化合成化合物与酶活性位点之间的相互作用。

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