Abstract

We have synthesized a series of phosphoramidates containing a heterocyclic moiety with good yields (88–95%) by the reaction of (E)-5-benzylidene-3-((2-hydroxyethoxy)methyl)thiazolidine-2,4-dione with ethyl phosphorodichloridate followed by the reaction with various heterocyclic amines. The designed compounds were primarily screened for their ability to inhibit pancreatic α-amylase enzyme using in silico molecular docking approach. The compounds with good binding energies (−8.0 to −6.9 kcal/mol) when compared with standard drug, acarbose (−8.0 kcal/mol) were prompted for the synthesis. The structures of the newly prepared compounds were confirmed by their spectroscopic analyses. They were further screened in vitro for their inhibition toward α-amylase enzyme using acarbose as standard drug. All compounds exhibited moderate to good inhibition potential with IC₅₀ values in the range of 54.14 ± 0.35 to 185.04 ± 0.53 µg/mL when compared with the standard drug (IC₅₀, 50.47 ± 0.28 µg/mL). Especially, the compound (E)-2-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methoxy)ethyl ethyl 1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-ylphosphoramidate (6f) (IC₅₀, 54.14 ± 0.35 µg/mL) and (E)-2-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methoxy)ethyl ethyl benzo[d]thiazol-2-ylphosphoramidate (6c) (IC₅₀, 57.02 ± 0.32 µg/mL) exhibited the best inhibition among the synthesized compounds.

抽象的

通过（E）-5-亚苄基-3-（（2-羟基乙氧基）甲基）噻唑烷-2,4-二酮与二氯化磷乙酯，然后与各种杂环胺反应。使用计算机分子对接方法初步筛选了设计的化合物抑制胰腺α-淀粉酶的能力。与标准药物阿卡波糖（-8.0 kcal / mol）相比，具有良好结合能（-8.0至-6.9 kcal / mol）的化合物被提示合成。通过光谱分析证实了新制备的化合物的结构。在体外进一步筛选了它们对α的抑制作用-淀粉酶，以阿卡波糖为标准药物。与标准药物（IC ₅₀：50.47±0.28 µg / mL）相比，所有化合物均表现出中等至良好的抑制潜力，IC ₅₀值在54.14±0.35至185.04±0.53 µg / mL范围内。特别地，化合物（E）-2-（（（5-亚苄基-2,4-二氧噻唑啉-3-基）甲氧基）乙基乙基1,3-二甲基-2,6-二氧代-1,2,3,6-四氢嘧啶-4- ylphosphoramidate（6F）（IC ₅₀，54.14±0.35微克/毫升）和（E）-2 - （（5-苄基-2,4-二氧代噻唑-3-基）甲氧基）乙基乙基苯并[d]噻唑-2- ylphosphoramidate（图6c）（IC ₅₀，57.02±0.32微克/毫升）表现出的合成的化合物中最好的抑制。