苯并杂环类α-葡萄糖苷酶抑制剂研究进展
Recent Advances in Benzoheterocycle Heterocyclic Compounds as α-Glucosidase Inhibitors
DOI: 10.12677/pi.2025.144027, PDF,   
作者: 段如彬：内蒙古医科大学药学院，内蒙古 呼和浩特；韩晓燕, 乔博洋, 张 弘, 肖 斌*：内蒙古医科大学鄂尔多斯临床医学院中心实验室，内蒙古 鄂尔多斯
关键词: α-葡萄糖苷酶抑制剂；苯并杂环；调控血糖水平；人工合成；2型糖尿病 ；α-Glucosidase Inhibitors； Benzoheterocycle Scaffolds； Regulating Blood Glucose Levels； Synthetically Designed； Type 2 Diabetes Mellitus
摘要: 糖尿病是一种致病机理复杂的代谢性疾病，全球糖尿病患者的数量逐年上升，用于治疗糖尿病的卫生支出也大幅增长。α-葡萄糖苷酶抑制剂是治疗2型糖尿病的有效方式之一。苯并杂环结构具有广泛的药理学活性，人工合成的苯并杂环类α-葡萄糖苷酶抑制剂表现出显著的抑制活性，能够有效调控2型糖尿病餐后血糖水平。本文综述了近年来以苯并杂环为核心骨架的α-葡萄糖苷酶抑制剂的研究进展，为开发新型α-葡萄糖苷酶抑制剂提供参考。
Abstract: Diabetes mellitus is a complex metabolic disease with multifactorial pathogenesis, and its global prevalence has been increasing annually, leading to a substantial rise in healthcare expenditures for diabetes treatment. α-Glucosidase inhibitors are an effective therapeutic approach for type 2 diabetes mellitus. Benzoheterocycle exhibits diverse pharmacological activities, and synthetic Benzoheterocycle α-glucosidase inhibitors have demonstrated significant inhibitory activity, effectively regulating postprandial blood glucose levels in type 2 diabetes mellitus patients. This review summarizes recent advances in α-glucosidase inhibitors featuring benzoheterocycle as the core scaffold, providing insights for the development of novel α-glucosidase inhibitors.
文章引用：段如彬, 韩晓燕, 乔博洋, 张弘, 肖斌. 苯并杂环类α-葡萄糖苷酶抑制剂研究进展[J]. 药物资讯, 2025, 14(4): 227-244. https://doi.org/10.12677/pi.2025.144027

参考文献

[1] Ogurtsova, K., Guariguata, L., Barengo, N.C., Ruiz, P.L., Sacre, J.W., Karuranga, S., et al. (2022) IDF Diabetes Atlas: Global Estimates of Undiagnosed Diabetes in Adults for 2021. Diabetes Research and Clinical Practice, 183, Article 109118. [Google Scholar] [CrossRef] [PubMed]
[2] Mohajan, D. and Mohajan, H.K. (2024) Alpha-Glucosidase Inhibitors (AGIs): A New Class of Oral Medication for Treatment of Type 2 Diabetes Patients. Journal of Innovations in Medical Research, 3, 1-6. [Google Scholar] [CrossRef] 
[3] Khamees Thabet, H., Ragab, A., Imran, M., Helal, M.H., Ibrahim Alaqel, S., Alshehri, A., et al. (2024) Discovery of New Anti-Diabetic Potential Agents Based on Paracetamol Incorporating Sulfa-Drugs: Design, Synthesis, α-Amylase, and α-Glucosidase Inhibitors with Molecular Docking Simulation. European Journal of Medicinal Chemistry, 275, Article 116589. [Google Scholar] [CrossRef] [PubMed]
[4] Ayan, E.K., Çoban, G. and Soyer, Z. (2024) Design, Synthesis, Biological Evaluation, and Molecular Modeling Studies of Some Quinazolin-4(3 H)-One-Benzenesulfonamide Hybrids as Potential Α-Glucosidase Inhibitors. Journal of Biomolecular Structure and Dynamics, 1-21. [Google Scholar] [CrossRef] [PubMed]
[5] Dirir, A.M., Daou, M., Yousef, A.F. and Yousef, L.F. (2022) A Review of Alpha-Glucosidase Inhibitors from Plants as Potential Candidates for the Treatment of Type-2 Diabetes. Phytochemistry Reviews, 21, 1049-1079. [Google Scholar] [CrossRef] [PubMed]
[6] Hossain, U., Das, A.K., Ghosh, S. and Sil, P.C. (2020) An Overview on the Role of Bioactive Α-Glucosidase Inhibitors in Ameliorating Diabetic Complications. Food and Chemical Toxicology, 145, Article 111738. [Google Scholar] [CrossRef] [PubMed]
[7] Cesta, C.E., Rotem, R., Bateman, B.T., Chodick, G., Cohen, J.M., Furu, K., et al. (2024) Safety of GLP-1 Receptor Agonists and Other Second-Line Antidiabetics in Early Pregnancy. JAMA Internal Medicine, 184, 144-152. [Google Scholar] [CrossRef] [PubMed]
[8] Ullah, S., Waqas, M., Halim, S.A., Khan, I., Khalid, A., Abdalla, A.N., et al. (2023) Triazolothiadiazoles and Triazolothiadiazines as Potent α-Glucosidase Inhibitors: Mechanistic Insights from Kinetics Studies, Molecular Docking and Dynamics Simulations. International Journal of Biological Macromolecules, 250, Article 126227. [Google Scholar] [CrossRef] [PubMed]
[9] Powers, A.C. (2021) Type 1 Diabetes Mellitus: Much Progress, Many Opportunities. Journal of Clinical Investigation, 131, e142242. [Google Scholar] [CrossRef] [PubMed]
[10] Roep, B.O., Thomaidou, S., van Tienhoven, R. and Zaldumbide, A. (2021) Type 1 Diabetes Mellitus as a Disease of the β-Cell (do Not Blame the Immune System?). Nature Reviews Endocrinology, 17, 150-161. [Google Scholar] [CrossRef] [PubMed]
[11] Galicia-Garcia, U., Benito-Vicente, A., Jebari, S., Larrea-Sebal, A., Siddiqi, H., Uribe, K.B., et al. (2020) Pathophysiology of Type 2 Diabetes Mellitus. International Journal of Molecular Sciences, 21, Article 6275. [Google Scholar] [CrossRef] [PubMed]
[12] Padhi, S., Nayak, A.K. and Behera, A. (2020) Type II Diabetes Mellitus: A Review on Recent Drug Based Therapeutics. Biomedicine & Pharmacotherapy, 131, Article 110708. [Google Scholar] [CrossRef] [PubMed]
[13] Magkos, F., Hjorth, M.F. and Astrup, A. (2020) Diet and Exercise in the Prevention and Treatment of Type 2 Diabetes Mellitus. Nature Reviews Endocrinology, 16, 545-555. [Google Scholar] [CrossRef] [PubMed]
[14] Chivese, T., Hoegfeldt, C.A., Werfalli, M., Yuen, L., Sun, H., Karuranga, S., et al. (2022) IDF Diabetes Atlas: The Prevalence of Pre-Existing Diabetes in Pregnancy—A Systematic Review and Meta-Analysis of Studies Published during 2010-2020. Diabetes Research and Clinical Practice, 183, Article 109049. [Google Scholar] [CrossRef] [PubMed]
[15] Agrawal, N., Sharma, M., Singh, S. and Goyal, A. (2022) Recent Advances of α-Glucosidase Inhibitors: A Comprehensive Review. Current Topics in Medicinal Chemistry, 22, 2069-2086. [Google Scholar] [CrossRef] [PubMed]
[16] Bhatnagar, A. and Mishra, A. (2022) α-Glucosidase Inhibitors for Diabetes/Blood Sugar Regulation. In: Maheshwari, V.L. and Patil, R.H., Eds, Natural Products as Enzyme Inhibitors, Springer, 269-283. [Google Scholar] [CrossRef] 
[17] Reuser, A.J.J. and Wisselaar, H.A. (1994) An Evaluation of the Potential Side‐Effects of α‐Glucosidase Inhibitors Used for the Management of Diabetes Mellitus. European Journal of Clinical Investigation, 24, 19-24. [Google Scholar] [CrossRef] [PubMed]
[18] Liu, R.-Y., Wang, H., Zhang, Z.-Y., et al. (2022) Progress in Understanding Interaction of Polysaccharides with Intestinal Flora. Food Science, 43, 363-373.
[19] Kaku, K. (2014) Efficacy of Voglibose in Type 2 Diabetes. Expert Opinion on Pharmacotherapy, 15, 1181-1190. [Google Scholar] [CrossRef] [PubMed]
[20] Patil, V.M., Tilekar, K.N., Upadhyay, N.M. and Ramaa, C.S. (2022) Synthesis, in-Vitro Evaluation and Molecular Docking Study of N-Substituted Thiazolidinediones as α-Glucosidase Inhibitors. ChemistrySelect, 7, e202103848. [Google Scholar] [CrossRef] 
[21] Naresh, B. (2017) Biological Importance of Heterocyclic Compounds—A Review. International Journal of Advance Re-search and Innovative Ideas in Education, 3, 1235-1244.
[22] Wang, G., He, D., Li, X., Li, J. and Peng, Z. (2016) Design, Synthesis and Biological Evaluation of Novel Coumarin Thiazole Derivatives as α-Glucosidase Inhibitors. Bioorganic Chemistry, 65, 167-174. [Google Scholar] [CrossRef] [PubMed]
[23] Ibrar, A., Zaib, S., Khan, I., Shafique, Z., Saeed, A. and Iqbal, J. (2017) New Prospects for the Development of Selective Inhibitors of α-Glucosidase Based on Coumarin-Iminothiazolidinone Hybrids: Synthesis, In-Vitro Biological Screening and Molecular Docking Analysis. 81, 119-133. [Google Scholar] [CrossRef] 
[24] Gabr, M.T. (2018) Antioxidant, α-Glucosidase Inhibitory and in Vitro Antitumor Activities of Coumarin-Benzothiazole Hybrids. Heterocyclic Communications, 24, 243-247. [Google Scholar] [CrossRef] 
[25] Taha, M., Shah, S.A.A., Afifi, M., Imran, S., Sultan, S., Rahim, F., et al. (2018) Synthesis, α-Glucosidase Inhibition and Molecular Docking Study of Coumarin Based Derivatives. Bioorganic Chemistry, 77, 586-592. [Google Scholar] [CrossRef] [PubMed]
[26] Mendieta-Moctezuma, A., Rugerio-Escalona, C., Villa-Ruano, N., et al. (2019) Synthesis and Biological Evaluation of Novel Chromonyl Enaminones as α-Glucosidase Inhibitors. Medicinal Chemistry Research, 28, 831-848. [Google Scholar] [CrossRef] 
[27] Jamil, W., Shaikh, J., Yousuf, M., et al. (2022) Synthesis, Anti-Diabetic and in Silico QSAR Analysis of Flavone Hydrazide Schiff Base Derivatives. Journal of Biomolecular Structure and Dynamics, 40, 12723-12738. [Google Scholar] [CrossRef] [PubMed]
[28] Zeng, W., Han, C., Mohammed, S., Li, S., Song, Y., Sun, F., et al. (2024) Indole-Containing Pharmaceuticals: Targets, Pharmacological Activities, and SAR Studies. RSC Medicinal Chemistry, 15, 788-808. [Google Scholar] [CrossRef] [PubMed]
[29] Naureen, S., Noreen, S., Nazeer, A., Ashraf, M., Alam, U., Munawar, M.A., et al. (2015) Triarylimidazoles-Synthesis of 3-(4,5-Diaryl-1h-Imidazol-2-Yl)-2-Phenyl-1H-Indole Derivatives as Potent α-Glucosidase Inhibitors. Medicinal Chemistry Research, 24, 1586-1595. [Google Scholar] [CrossRef] 
[30] Solangi, M., Mohammed Khan, K., Saleem, F., Hameed, S., Iqbal, J., et al. (2020) Indole Acrylonitriles as Potential Anti-Hyperglycemic Agents: Synthesis, Α-Glucosidase Inhibitory Activity and Molecular Docking Studies. Bioorganic & Medicinal Chemistry, 28, Article 115605. [Google Scholar] [CrossRef] [PubMed]
[31] Mal, S., Malik, U., Mahapatra, M., Mishra, A., Pal, D. and Paidesetty, S.K. (2022) A Review on Synthetic Strategy, Molecular Pharmacology of Indazole Derivatives, and Their Future Perspective. Drug Development Research, 83, 1469-1504. [Google Scholar] [CrossRef] [PubMed]
[32] Mphahlele, M.J., Magwaza, N.M., Gildenhuys, S. and Setshedi, I.B. (2020) Synthesis, α-Glucosidase Inhibition and Antioxidant Activity of the 7-Carbo-Substituted 5-Bromo-3-Methylindazoles. Bioorganic Chemistry, 97, Article 103702. [Google Scholar] [CrossRef] [PubMed]
[33] Shah, K., Chhabra, S., Shrivastava, S.K. and Mishra, P. (2013) Benzimidazole: A Promising Pharmacophore. Medicinal Chemistry Research, 22, 5077-5104. [Google Scholar] [CrossRef] 
[34] Arshad, T., Khan, K.M., Rasool, N., Salar, U., Hussain, S., Tahir, T., et al. (2016) Syntheses, in Vitro Evaluation and Molecular Docking Studies of 5-Bromo-2-Aryl Benzimidazoles as α-Glucosidase Inhibitors. Medicinal Chemistry Research, 25, 2058-2069. [Google Scholar] [CrossRef] 
[35] Özil, M., Emirik, M., Etlik, S.Y., Ülker, S. and Kahveci, B. (2016) A Simple and Efficient Synthesis of Novel Inhibitors of Alpha-Glucosidase Based on Benzimidazole Skeleton and Molecular Docking Studies. Bioorganic Chemistry, 68, 226-235. [Google Scholar] [CrossRef] [PubMed]
[36] Arshad, T., Khan, K.M., Rasool, N., Salar, U., Hussain, S., Asghar, H., et al. (2017) 5-Bromo-2-Aryl Benzimidazole Derivatives as Non-Cytotoxic Potential Dual Inhibitors of α-Glucosidase and Urease Enzymes. Bioorganic Chemistry, 72, 21-31. [Google Scholar] [CrossRef] [PubMed]
[37] Özil, M., Parlak, C. and Baltaş, N. (2018) A Simple and Efficient Synthesis of Benzimidazoles Containing Piperazine or Morpholine Skeleton at C-6 Position as Glucosidase Inhibitors with Antioxidant Activity. Bioorganic Chemistry, 76, 468-477. [Google Scholar] [CrossRef] [PubMed]
[38] Aroua, L.M., Almuhaylan, H.R., Alminderej, F.M., Messaoudi, S., Chigurupati, S., Al-mahmoud, S., et al. (2021) A Facile Approach Synthesis of Benzoylaryl Benzimidazole as Potential α-Amylase and α-Glucosidase Inhibitor with Antioxidant Activity. Bioorganic Chemistry, 114, Article 105073. [Google Scholar] [CrossRef] [PubMed]
[39] Halappanavar, V., Teli, S., Sannakki, H.B. and Teli, D. (2025) Quinazoline Scaffold as a Target for Combating Microbial Resistance: Synthesis and Antimicrobial Profiling of Quinazoline Derivatives. Results in Chemistry, 13, Article 101955. [Google Scholar] [CrossRef] 
[40] Abuelizz, H.A., Anouar, E.H., Ahmad, R., Azman, N.I.I.N., Marzouk, M. and Al-Salahi, R. (2019) Triazoloquinazolines as a New Class of Potent α-Glucosidase Inhibitors: In Vitro Evaluation and Docking Study. PLOS ONE, 14, e0220379. [Google Scholar] [CrossRef] [PubMed]
[41] Wei, M., Chai, W., Wang, R., Yang, Q., Deng, Z. and Peng, Y. (2017) Quinazolinone Derivatives: Synthesis and Comparison of Inhibitory Mechanisms on α-Glucosidase. Bioorganic & Medicinal Chemistry, 25, 1303-1308. [Google Scholar] [CrossRef] [PubMed]
[42] Faizan, S., Roohi, T.F., Raju, R.M., Sivamani, Y. and BR, P.K. (2023) A Century-Old One-Pot Multicomponent Biginelli Reaction Products Still Finds a Niche in Drug Discoveries: Synthesis, Mechanistic Studies and Diverse Biological Activities of Dihydropyrimidines. Journal of Molecular Structure, 1291, Article 136020. [Google Scholar] [CrossRef] 
[43] Anjali, Kamboj, P. and Amir, M. (2025) Synthetic Methods of Quinoxaline Derivatives and Their Potential Anti-Inflammatory Properties. Mini-Reviews in Medicinal Chemistry, 25, 138-162. [Google Scholar] [CrossRef] [PubMed]
[44] Satyanarayana, N., Sree, B.R., Sathish, K., Nagaraju, S., Divakar, K., Pawar, R., et al. (2022) Synthesis of 2-Styryl-Quinazoline and 3-Styryl-Quinoxaline Based Sulfonate Esters via Sp3 C-H Activation and Their Evaluation for α-Glucosidase Inhibition. New Journal of Chemistry, 46, 5162-5170. [Google Scholar] [CrossRef] 
[45] Khalid, Z., Shafqat, S.S., Ahmad, H.A., Rehman, H.M., Munawar, M.A., Ahmad, M., et al. (2022) Synthesis of 1,2,3-Benzotriazin-4(3H)-One Derivatives as α-Glucosidase Inhibitor and Their In-Silico Study. Medicinal Chemistry Research, 31, 819-831. [Google Scholar] [CrossRef] 
[46] Gandhi, A.K., Kang, J., Havens, C.G., Conklin, T., Ning, Y., Wu, L., et al. (2013) Immunomodulatory Agents Lenalidomide and Pomalidomide Co-Stimulate T Cells by Inducing Degradation of T Cell Repressors Ikaros and Aiolos via Modulation of the E3 Ubiquitin Ligase Complex CRL4CRBN. British Journal of Haematology, 164, 811-821. [Google Scholar] [CrossRef] [PubMed]
[47] Latif, T., Chauhan, N., Khan, R., Moran, A. and Usmani, S.Z. (2012) Thalidomide and Its Analogues in the Treatment of Multiple Myeloma. Experimental Hematology & Oncology, 1, Article No. 27. [Google Scholar] [CrossRef] [PubMed]
[48] Askarzadeh, M., Azizian, H., Adib, M., Mohammadi-Khanaposhtani, M., Mojtabavi, S., Faramarzi, M.A., et al. (2022) Design, Synthesis, in Vitro α-Glucosidase Inhibition, Docking, and Molecular Dynamics of New Phthalimide-Benzenesulfonamide Hybrids for Targeting Type 2 Diabetes. Scientific Reports, 12, Article No. 10569. [Google Scholar] [CrossRef] [PubMed]
[49] Kumar, G., Singh, N.P. and Kumar, K. (2021) Recent Advancement of Synthesis of Isatins as a Versatile Pharmacophore: A Review. Drug Research, 71, 115-121. [Google Scholar] [CrossRef] [PubMed]
[50] Rahim, F., Malik, F., Ullah, H., Wadood, A., Khan, F., Javid, M.T., et al. (2015) Isatin Based Schiff Bases as Inhibitors of α-Glucosidase: Synthesis, Characterization, in Vitro Evaluation and Molecular Docking Studies. Bioorganic Chemistry, 60, 42-48. [Google Scholar] [CrossRef] [PubMed]
[51] Wang, G., Peng, Y., Xie, Z., Wang, J. and Chen, M. (2017) Synthesis, α-Glucosidase Inhibition and Molecular Docking Studies of Novel Thiazolidine-2,4-Dione or Rhodanine Derivatives. MedChemComm, 8, 1477-1484. [Google Scholar] [CrossRef] [PubMed]
[52] Solangi, M., Kanwal, Khan, K.M., Chigurupati, S., Saleem, F., Qureshi, U., et al. (2022) Isatin Thiazoles as Antidiabetic: Synthesis, in Vitro Enzyme Inhibitory Activities, Kinetics, and in Silico Studies. Archiv der Pharmazie, 355, Article 2100481. [Google Scholar] [CrossRef] [PubMed]
[53] Adalat, B., Rahim, F., Taha, M., Hayat, S., Iqbal, N., Ali, Z., et al. (2022) Synthesis of Benzofuran-Based Schiff Bases as Anti-Diabetic Compounds and Their Molecular Docking Studies. Journal of Molecular Structure, 1265, Article 133287. [Google Scholar] [CrossRef] 
[54] Guo, F., Zhang, S., Yan, X., Dan, Y., Wang, J., Zhao, Y., et al. (2019) Bioassay-Guided Isolation of Antioxidant and α-Glucosidase Inhibitory Constituents from Stem of Vigna Angularis. Bioorganic Chemistry, 87, 312-320. [Google Scholar] [CrossRef] [PubMed]
[55] Sun, H., Ding, W., Song, X., Wang, D., Chen, M., Wang, K., et al. (2017) Synthesis of 6-Hydroxyaurone Analogues and Evaluation of Their α-Glucosidase Inhibitory and Glucose Consumption-Promoting Activity: Development of Highly Active 5,6-Disubstituted Derivatives. Bioorganic & Medicinal Chemistry Letters, 27, 3226-3230. [Google Scholar] [CrossRef] [PubMed]
[56] Mphahlele, M.J., Choong, Y.S., Maluleka, M.M. and Gildenhuys, S. (2020) Synthesis, in Vitro Evaluation and Molecular Docking of the 5-Acetyl-2-Aryl-6-Hydroxybenzo[b]Furans against Multiple Targets Linked to Type 2 Diabetes. Biomolecules, 10, Article 418. [Google Scholar] [CrossRef] [PubMed]
[57] Delogu, G.L., Era, B., Floris, S., Medda, R., Sogos, V., Pintus, F., et al. (2021) A New Biological Prospective for the 2-Phenylbenzofurans as Inhibitors of α-Glucosidase and of the Islet Amyloid Polypeptide Formation. International Journal of Biological Macromolecules, 169, 428-435. [Google Scholar] [CrossRef] [PubMed]