Synthesis, PASS Prediction, Molecular Docking and Pharmacokinetic Studies of Newer 1,3,4-Thiadiazole Hybrids Of P-Thymol as Antidiabetic Agents
Keywords:
1,3,4-thiadiazole, Para-thymol, α-amylase inhibitor,, Pharmacokinetic study, AntidiabeticAbstract
A novel series of amide analogs of p-thymol, clubbed with 1,3,4-thiadiazole (8a-8l) was developed and synthesized. This was achieved by attaching the phenolic group of the naturally occurring p-thymol core to 1,3,4-thiadiazole, followed by coupling with various substituted acyl chloride moieties through an amino linker, resulting in a good yield (83-91 %). The identities of all the synthesized compounds were confirmed using spectroscopic methods, including 1H NMR, 13C NMR, mass spectrometry, and FT-IR. In this study, the biological activity profile of the designed analogs was predicted using the PASS prediction tool, indicating their potential antidiabetic activity. The compounds were synthesized, and their activities were experimentally assessed at a concentration of 62.5 500 µL. The observed experimental activity was aligned with the predictions made by PASS. Molecular docking studies were conducted to determine the binding free energies of all the compounds at the active site of isomaltase from S. cerevisiae (PDB ID: 3A47). Compounds 8a and 8d exhibited excellent docking scores. The synthesized compounds were evaluated for their in vitro antidiabetic activity and showed moderate-to-good results. Notably, compounds 8a, 8e, 8j, and 8l exhibited significant antidiabetic activity compared with the positive standard acarbose. A comparative analysis of Lipinski’s parameters and compound activity showed that all compounds adhered to Lipinski’s rule of five.
Downloads
Metrics
References
Ortiz-Martínez, M., González-González, M., Martagón, A. J., Hlavinka, V., Willson, R. C., & Rito-Palomares, M. (2022). Current Diabetes Reports, 22(3), 95–115. https://doi.org/10.1007/s11892-022-01453-4
Patil, S. R., Chavan, A. B., Bhopale, J. V., Patel, A. M., & Chavan, P. D. (2023). Journal for Research in Applied Sciences and Biotechnology, 2(4), 73–79. https://doi.org/10.55544/jrasb.2.4.9
Nathan, D. M., Davidson, M. B., DeFronzo, R. A., Heine, R. J., Henry, R. R., Pratley, R., & Zinman, B. (2007). Diabetes care, 30(3), 753-759.https://doi: 10.2337/dc07-9920
Patel, A., Sindhu, D. K., Arora, N., Singh, R. P., Pruthi, V., & Pruthi, P. A. (2015). Bioresource Technology, 197, 91-98. https://doi.org/10.1016/j.biortech.2015.08.039
Chandrasekaran, P., & Weiskirchen, R. (2024). The role of obesity in type 2 diabetes mellitus—An overview. International journal of molecular sciences, 25(3), 1882. https://doi.org/10.3390/ijms25031882
Sowers, J. R. (2013). Hypertension, 61(5), 943-947. https://doi.org/10.1161/HYPERTENSIONAHA.111.00612
Tienda-Vázquez, M. A., Elizondo-Luévano, J. H., Parra-Saldívar, R., Melchor-Martínez, E. M., Lara-Ortiz, J. S., Scheckhuber, C. Q., & Luna-Sosa, B. (2023). Processes, 11(5), 1299. https://doi.org/10.3390/pr11051299
Mishra, A. K., Pannu, A., Sahoo, P. K., Pandey, M., & Dewangan, H. K. (2024). Current Traditional Medicine, 10(3). https://doi.org/10.2174/2215083810666230501212125
Alqathama, A., Makkawi, S., Alluhiabi, G., Aljahani, L., Jabal, S., Alhomoud, F., Khan, O., & Baghdadi, H. (2020). BMC Complementary Medicine and Therapies, 20(1). https://doi.org/10.1186/s12906-020-2854-4
Bourhia, M., Ait Haj Said, A., Ali Naser, F., Khlil, N., Benbacer, L., El Gueddari, F., Mostafa Abdelmageed, W., Naamane, A., Mohammed Almarfadi, O., & Abdelaziz Shahat, A. (2019). Evidence-Based Complementary and Alternative Medicine, 2019(1), 1–9. https://doi.org/10.1155/2019/1613457
Cox-Georgian, D., Ramadoss, N., Dona, C., & Basu, C. (2019). Medicinal plants: from farm to pharmacy, 333-359. https://doi.org/10.1007/978-3-030-31269-5_15
McCadden, C. A., Alsup, T. A., Ghiviriga, I., & Rudolf, J. D. (2025). Biocatalytic diversification of abietic acid in Streptomyces. Journal of Industrial Microbiology and Biotechnology, kuaf003. https://doi.org/10.1093/jimb/kuaf003
Masyita, A., Mustika Sari, R., Dwi Astuti, A., Yasir, B., Rahma Rumata, N., Emran, T. B., Nainu, F., & Simal-Gandara, J. (2022). Food Chemistry: X, 13, 100217. https://doi.org/10.1016/j.fochx.2022.100217
Minakshi, Prakash, S., Kumari, H., & Kumar, A. (2024). Natural Bioactive Products from Marine Fungi Against Bacterial Infection. In Fungi Bioactive Metabolites: Integration of Pharmaceutical Applications (pp. 241-259). Singapore: Springer Nature Singapore. https://doi.org/ 10.1007/978-981-99-5696-8_8
Alagawany, M., Abdelnour, S. A., Farag, M. R., & Elnesr, S. S. (2020). Reviews in Aquaculture, 13(1), 632–641. https://doi.org/10.1111/raq.12490
Ezzat Abd El-Hack, M., Alagawany, M., Ragab Farag, M., Tiwari, R., Karthik, K., Dhama, K., Zorriehzahra, J., & Adel, M. (2016). Journal of Essential Oil Research, 28(5), 365–382. https://doi.org/10.1080/10412905.2016.1153002
Panigrahi, A., & Pulukuri, K. K. (2024). Streamlined Synthesis of Eudesmane Sesquiterpenoids through Site-switchable Olefin Functionalization Strategy. https://doi.org/ 10.26434/chemrxiv-2023-3fldg-v4
ZHANG, L., LI, Y., & MAO, J. (2024). Research progress on natural products against hepatocellular carcinoma. Biocell, 48(6). https://doi.org/ 10.32604/biocell.2024.050396
Palamarchuk, I. V., Shulgau, Z. T., Dautov, A. Y., Sergazy, S. D., & Kulakov, I. V. (2022). Organic & Biomolecular Chemistry, 20(45), 8962-8976. https://doi.org/10.1039/D2OB01772E
Gummidi, L., Kerru, N., Ebenezer, O., Awolade, P., Sanni, O., Islam, M. S., & Singh, P. (2021). Bioorganic Chemistry, 115, 105210.https://doi.org/10.1016/j.bioorg.2021.105210
Ali, Z., Rehman, W., Rasheed, L., Alzahrani, A. Y., Ali, N., Hussain, R., ... & Abdellattif, M. H. (2024). ACS omega, 9(7), 7480-7490.https://doi.org/10.1021/acsomega.3c05854
Worthington, V. (1993). Worthington enzyme manual, 36-41.
Ahmed, I. T. (2007). Transition Metal Chemistry, 32(5), 674-682.https://doi.org/10.1007/s11243-007-0232-4
Poroikov, V. V., Filimonov, D. A., Borodina, Y. V., Lagunin, A. A., & Kos, A. (2000). Journal of chemical information and computer sciences, 40(6), 1349-1355. https://doi.org/10.1021/ci000383k
Marwaha, A., Goel, R. K., & Mahajan, M. P. (2007). Bioorganic & Medicinal Chemistry Letters, 17(18), 5251-5255. https://doi.org/10.1016/j.bmcl.2007.06.071
Trott, O., & Olson, A. J. (2010). Journal of computational chemistry, 31(2), 455-461. https://doi.org/10.1002/jcc.21334
MarvinSketch 19.19.0, 2019, ChemAxon.
Biovia, Dassault Systèmes, BIOVIA Discovery Studio Visualizer 2017, v.12.0., San Diego: DassaultSystèmes, (2016).
Daina, A., Michielin, O., & Zoete, V. (2017). SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific reports, 7(1), 1-13. https://doi.org/10.1038/srep42717
Zhao, Y. H., Abraham, M. H., Le, J., Hersey, A., Luscombe, C. N., Beck, G., & Cooper, I. (2002). Pharmaceutical research, 19(10), 1446-1457.https://doi.org/10.1023/A:1020444330011
Bojarska, J., Remko, M., Breza, M., Madura, I. D., Kaczmarek, K., Zabrocki, J., & Wolf, W. M. (2020). Molecules, 25(5), 1135. https://doi.org/10.3390/molecules25051135
Ames, B. N., Gurney, E. G., Miller, J. A., & Bartsch, H. (1972). Proceedings of the National Academy of Sciences, 69(11), 3128-3132.https://doi.org/10.1073/pnas.69.11.3128
Downloads
Published
How to Cite
Issue
Section
License
This work is licensed under a Creative Commons Attribution 4.0 International License.
You are free to:
- Share — copy and redistribute the material in any medium or format
- Adapt — remix, transform, and build upon the material for any purpose, even commercially.
Terms:
- Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
- No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.
