Design and Synthesis of Novel Imidazo[2,1-b]thiazole-Based 4- Thiazolidinone Derivatives as Potent α-Glucosidase Inhibitors

Year 2025, Volume: 55 Issue: 2, 183 - 190, 23.09.2025

Efe Doğukan Dincel , Gözde Hasbal Çelikok , Tuğba Yılmaz Özden , Nuray Ulusoy Güzeldemirci

https://doi.org/10.26650/IstanbulJPharm.2025.1600357

Abstract

Background and Aims: Inhibiting the α-glucosidase reduces the rate at which glucose is absorbed, helping to control blood sugar levels. This strategy presents a potential alternative for managing type 2 diabetes, offering a promising approach with fewer adverse effects compared with conventional treatments. Based on this, we synthesised novel imidazo[2,1-b]thiazole-based 4-thiazolidinone derivatives (5a-e) and eval uated them for their α-glucosidase inhibitory activities.

Methods: Structural confirmation of the synthesised compounds was carried out using various spectro scopic techniques, including IR, ¹H-NMR and ¹³C-NMR spectroscopy, elemental analysis and ESI-MS. The newly synthesised compounds were subjected to in vitro evaluation to assess their inhibitory effects on α-glucosidase activity.

Results: Spectroscopic analyses confirmed the successful synthesis of the target compounds. Among them, compound 5e exhibited the most potent α-glucosidase inhibitory effect, with a half-maximal inhibitory concentration (IC₅₀) value of 115.94 ± 0.58 µM, outperforming the standard drug acarbose, which showed an IC₅₀ of 179.25 ± 3.41 µM.

Conclusion: In summary, a series of novel imidazo[2,1-b]thiazole-based 4-thiazolidinone derivatives (5a-e) were successfully synthesised, among which compound 5e emerged as the most potent α-glucosidase inhibitor, surpassing the activity of the reference drug acarbose. These findings position compound 5e as a promising lead candidate for developing new α-glucosidase inhibitory agents. To fully assess the therapeutic value of this scaffold, further in vitro investigations on structurally related analogs, followed by comprehensive in vivo assessments, are warranted.

Keywords

Synthesis , Imidazothiazole , 4-Thiazolidinone , α-Glucosidase Inhibitory Activity

References

• Andreani, A., Granaiola, M., Leoni, A., Locatelli, A., Morigi, R., & Rambaldi, M. (2001). Synthesis and antitubercular activity of imidazo[2,1-b]thiazoles. European Journal of Medicinal Chemistry, 36(9), 743–746. https://doi.org/10.1016/s0223-5234(01)01266-1 google scholar
• Bothon, F. T., Debiton, E., Avlessi, F., Forestier, C., Teulade, J. C., & Sohounhloue, D. K. (2013). In vitro biological effects of two anti-diabetic medicinal plants used in Benin as folk medicine. BMC Alternative and Complementary Medicine, 13, 51. https://doi.org/10.1186/1472-6882-13-51 google scholar
• Cihan-Ustundag, G., Gursoy, E., Naesens, L., Ulusoy-Guzeldemirci, N., & Capan, G. (2016). Synthesis and antiviral properties of novel indole-based thiosemicarbazides and 4-thiazolidinones. Bioorganic & Medicinal Chemistry, 24(2), 240– 246. https://doi.org/10.1016/j.bmc.2015.12.008 google scholar
• Deep, A., Jain, S., Sharma, P. C., Phogat, P., & Malhotra, M. (2011). Synthesis of 2-(aryl)-5-(arylidene)-4-thiazolidinone derivatives with potential analgesic and anti-inflammatory activity. Medicinal Chemistry Research, 21(8), 1652–1659. https://doi.org/10.1007/s00044-011-9679-0 google scholar
• Desouza, C. V., & Shivaswamy, V. (2010). Pioglitazone in the treatment of type 2 diabetes: safety and efficacy review. Clinical Medicine Insights: Endocrinology and Diabetes, 3, 43–51. https://doi.org/10.4137/cmed.s5372 google scholar
• Dincel, E. D., Hasbal-Celikok, G., Yilmaz-Ozden, T., & Ulusoy-Güzeldemirci, N. (2021). Design, biological evaluation, molecular docking study and in silico ADME prediction of novel imidazo[2,1-b]thiazole derivatives as a novel class of α-glucosidase inhibitors. Journal of Molecular Structure, 1245. https://doi.org/10. 1016/j.molstruc.2021.131260 google scholar
• Dincel, E. D., Hasbal-Celikok, G., Yilmaz-Ozden, T., & Ulusoy-Güzeldemirci, N. (2022). Design, synthesis, biological evaluation, molecular docking, and dynamic simulation study of novel imidazo[2,1-b]thiazole derivatives as potent antioxidant agents. Journal of Molecular Structure, 1258. https://doi.org/10.1016/j.molstruc. 2022.132673 google scholar
• Fischer, W., Bodewei, R., & Satzinger, G. (1992). Anticonvulsant and sodium channel blocking effects of ralitoline in different screening models. Naunyn-Schmiedeberg’s Archives of Pharmacology, 346(4), 442–452. https://doi.org/10. 1007/BF00171088 google scholar
• Ghani, U. (2015). Re-exploring promising alpha-glucosidase inhibitors for potential development into oral anti-diabetic drugs: Finding needle in the haystack. Eur Journal of Medicinal Chemistry, 103, 133–162. https://doi.org/10.1016/j.ejmech. 2015.08.043 google scholar
• Gillis, E. P., Eastman, K. J., Hill, M. D., Donnelly, D. J., & Meanwell, N. A. (2015). Applications of Fluorine in Medicinal Chemistry. Journal of Medicinal Chemistry, 58(21), 8315–8359. https://doi.org/10.1021/acs.jmedchem.5b00258 google scholar
• Guariguata, L., Whiting, D. R., Hambleton, I., Beagley, J., Linnenkamp, U., & Shaw, J. E. (2014). Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Research and Clinical Practice, 103(2), 137–149. https://doi.org/ 10.1016/j.diabres.2013.11.002 google scholar
• Harraga, S., Nicod, L., Drouhin, J. P., Xicluna, A., Panouse, J. J., Seilles, E., & Robert, J. F. (1994). Imidazo[2,1-b]thiazole derivatives. XI. Modulation of the CD2-receptor of human T trypsinized lymphocytes by several imidazo[2,1-b]thiazoles. European Journal of Medicinal Chemistry, 29(4), 309–315. https://doi.org/10.1016/ 0223-5234(94)90101-5 google scholar
• Havrylyuk, D., Mosula, L., Zimenkovsky, B., Vasylenko, O., Gzella, A., & Lesyk, R. (2010). Synthesis and anticancer activity evaluation of 4-thiazolidinones containing benzothiazole moiety. European Journal of Medicinal Chemistry, 45(11), 5012– 5021. https://doi.org/10.1016/j.ejmech.2010.08.008 google scholar
• Javid, M. T., Rahim, F., Taha, M., Rehman, H. U., Nawaz, M., Wadood, A., Imran, S., Uddin, I., Mosaddik, A., & Khan, K. M. (2018). Synthesis, in vitro alpha-glucosidase inhibitory potential and molecular docking study of thiadiazole analogs. Bioorganic Chemistry, 78, 201–209. https://doi.org/10.1016/j.bioorg.2018.03.022 google scholar
• Jeschke, P. (2004). The unique role of fluorine in the design of active ingredients for modern crop protection. Chembiochem, 5(5), 571–589. https://doi.org/10.1002/ cbic.200300833 google scholar
• Kasturi, S., Surarapu, S., Uppalanchi, S., Anireddy, J. S., Dwivedi, S., Anantaraju, H. S., Perumal, Y., Sigalapalli, D. K., Babu, B. N., & Ethiraj, K. S. (2017). Synthesis and alpha-glucosidase inhibition activity of dihydroxy pyrrolidines. Bioorganic & Medicinal Chemistry Letters, 27(12), 2818–2823. https://doi.org/10.1016/j.bmcl. 2017.04.078 google scholar
• Kickhöfen, B., & Kröhnke, F. (1955). Zur Kenntnis des Imidazothiazol‐Ringsystems. Chemische Berichte, 88(7), 1109–1114. https://doi.org/10.1002/cber.19550880726 google scholar
• Loscher, W., von Hodenberg, A., Nolting, B., Fassbender, C. P., & Taylor, C. (1991). Rali-toline: a reevaluation of anticonvulsant profile and determination of "active" plasma concentrations in comparison with prototype antiepileptic drugs in mice. Epilepsia, 32(4), 560–568. https://doi.org/10.1111/j.1528-1157.1991.tb04693. x google scholar
• Omar, K., Geronikaki, A., Zoumpoulakis, P., Camoutsis, C., Sokovic, M., Ciric, A., & Glam-oclija, J. (2010). Novel 4-thiazolidinone derivatives as potential antifungal and antibacterial drugs. Bioorganic & Medicinal Chemistry, 18(1), 426–432. https:// doi.org/10.1016/j.bmc.2009.10.041 google scholar
• Playford, R. J., Pither, C., Gao, R., & Middleton, S. J. (2013). Use of the alpha glucosidase inhibitor acarbose in patients with 'Middleton syndrome': normal gastric anatomy but with accelerated gastric emptying causing postprandial reactive hypoglycemia and diarrhea. Canadian Journal of Gastroenterology and Hepatology, 27(7), 403–404. https://doi.org/10.1155/2013/791803 google scholar
• Reaven, G. M. (1988). Banting lecture 1988. Role of insulin resistance in human disease. Diabetes, 37(12), 1595–1607. https://doi.org/10.2337/diab.37.12.1595 google scholar
• Robert, J. F., Xicluna, A., & J.J., P. (1975). Derivatives of imidazo[2,1-b]thiazole. II. Synthesis of imidazo[2,1-b]thiazole derivatives with carbonyl side chains from 2 aminothiazole. European Journal of Medicinal Chemistry, 10, 59–64. google scholar
• Sun, H., Saeedi, P., Karuranga, S., Pinkepank, M., Ogurtsova, K., Duncan, B. B., Stein, C., Basit, A., Chan, J. C. N., Mbanya, J. C., Pavkov, M. E., Ramachandaran, A., Wild, S. H., James, S., Herman, W. H., Zhang, P., Bommer, C., Kuo, S., Boyko, E. J., & Magliano, D. J. (2022). IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Research and Clinical Practice, 183, 109119. https://doi.org/10.1016/j.diabres.2021.109119 google scholar
• Tratrat, C., Petrou, A., Geronikaki, A., Ivanov, M., Kostic, M., Sokovic, M., Vizirianakis, I. S., Theodoroula, N. F., & Haroun, M. (2022). Thiazolidin-4-Ones as Potential Antimicrobial Agents: Experimental and In Silico Evaluation. Molecules, 27(6). https://doi.org/10.3390/molecules27061930 google scholar
• Trotsko, N. (2021). Antitubercular properties of thiazolidin-4-ones - A review. European Journal of Medicinal Chemistry, 215, 113266. https://doi.org/10.1016/j. ejmech.2021.113266 google scholar
• Ulusoy Guzeldemirci, N., Karaman, B., & Kucukbasmaci, O. (2017). Antibacterial, Antitubercular and Antiviral Activity Evaluations of Some Arylidenehydrazide google scholar
• Derivatives Bearing Imidazo[2,1-b]thiazole Moiety. Turkish Journal of Pharmaceutical Sciences, 14(2), 157–163. https://doi.org/10.4274/tjps.25743 google scholar
• Wei, X., Wang, P., Liu, F., Ye, X., & Xiong, D. (2023). Drug Discovery Based on Fluorine-Containing Glycomimetics. Molecules, 28(18). https://doi.org/10.3390/ molecules28186641 google scholar
• Wright, E. M., Martin, M. G., & Turk, E. (2003). Intestinal absorption in health and disease–sugars. Best Practice & Research Clinical Gastroenterology, 17(6), 943– 956. https://doi.org/10.1016/s1521-6918(03)00107-0 google scholar