Phongphane Lacksany, Mohd Radzuan Siti Nurshahira, Abu Bakar Mohamad Hafizi, Che Omar Mohammad Tasyriq, Supratman Unang, Harneti Desi, A Wahab Habibah, Azmi Mohamad Nurul
Natural Products and Synthesis Organic Research Laboratory (NPSO), School of Chemical Sciences, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia.
Bioprocess Technology Division, School of Industrial Technology, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia.
Comput Biol Chem. 2023 Oct;106:107938. doi: 10.1016/j.compbiolchem.2023.107938. Epub 2023 Aug 2.
In our effort to develop potent anti-hyperglycemic compounds with inhibitory activity against α-amylase and α-glucosidase, a series of novel quinoxaline-isoxazole moieties were synthesized. The novel quinoxaline-isoxazole derivatives were assessed in vitro for their anti-hyperglycemic activities on α-amylase and α-glucosidase inhibitions. The results revealed promising IC values compared to acarbose as a positive control for α-amylase and α-glucosidase. Among them, N-Ethyl-7-chloro-3-((3-phenylisoxazol-5-yl)methoxy)quinoxalin-2-amine 5b showed dual inhibitory with IC of 24.0 µM for α-amylase and 41.7 µM for α-glucosidase. In addition, N-Ethyl-7-methoxy-3-((3-(2-chlorophenyl)isoxazol-5-yl)methoxy)quinoxalin-2-amine 5j also had dual bioactivities against α-amylase and α-glucosidase with IC of 17.0 and 40.1 µM, respectively. Nevertheless, two more compounds N-Ethyl-7-cyano-3-((3-phenylisoxazol-5-yl)methoxy)quinoxaline-2-amine 5e showed strong mono-inhibition for α-glucosidase with IC of 16.6 µM followed by N-Ethyl-7-methoxy-3-((3-phenylisoxazol-5-yl)methoxy)quinoxalin-2-amine 5 f with IC of 18.6 µM. The molecular docking study for α-glucosidase inhibitor provided the binding energy ranging from 8.3 to 9.1 kcal/mol and α-amylase inhibitor showed the binding energy score at 8.4 and 8.5 kcal/mol. The dual inhibitions nature of 5b and 5j were further analyzed and confirmed via molecular dynamics including the stability of the compound, interaction energy, binding free energy, and the interaction residue analysis using the MM-GBSA approach. The results showed that compound 5j was the most potent compound. Lastly, the drug-likeness properties were also evaluated with all synthesized compounds 5a-5j and the results reveal that all potent compounds meet Lipinski's rules of five.
为了开发对α-淀粉酶和α-葡萄糖苷酶具有抑制活性的强效抗高血糖化合物，我们合成了一系列新型喹喔啉-异恶唑部分。对新型喹喔啉-异恶唑衍生物进行了体外α-淀粉酶和α-葡萄糖苷酶抑制活性的抗高血糖活性评估。与作为α-淀粉酶和α-葡萄糖苷酶阳性对照的阿卡波糖相比，结果显示出有前景的IC值。其中，N-乙基-7-氯-3-((3-苯基异恶唑-5-基)甲氧基)喹喔啉-2-胺5b对α-淀粉酶的IC为24.0 μM，对α-葡萄糖苷酶的IC为41.7 μM，表现出双重抑制作用。此外，N-乙基-7-甲氧基-3-((3-(2-氯苯基)异恶唑-5-基)甲氧基)喹喔啉-2-胺5j对α-淀粉酶和α-葡萄糖苷酶也具有双重生物活性，IC分别为17.0和40.1 μM。然而，另外两种化合物N-乙基-7-氰基-3-((3-苯基异恶唑-5-基)甲氧基)喹喔啉-2-胺5e对α-葡萄糖苷酶表现出强烈的单抑制作用，IC为16.6 μM，其次是N-乙基-7-甲氧基-3-((3-苯基异恶唑-5-基)甲氧基)喹喔啉-2-胺5f，IC为18.6 μM。α-葡萄糖苷酶抑制剂的分子对接研究提供了8.3至9.1 kcal/mol的结合能，α-淀粉酶抑制剂的结合能分数为8.4和8.5 kcal/mol。通过分子动力学进一步分析并确认了5b和5j的双重抑制性质，包括化合物的稳定性、相互作用能、结合自由能以及使用MM-GBSA方法进行的相互作用残基分析。结果表明化合物5j是最有效的化合物。最后，还对所有合成化合物5a - 5j的类药性质进行了评估，结果表明所有有效化合物均符合Lipinski的五规则。
