A Novel Benzenesulfonylurea-Substituted Pyridazinone Derivative with Antidiabetic Effect as the Peroxisome Proliferator-activated Receptor (PPAR-γ) Agonist
DOI:
https://doi.org/10.15408/jkv.v11i1.42187Keywords:
ADMET, schiff base condensation, molecular docking, PPAR-γ agonistAbstract
Peroxisome Proliferator-activated Receptor (PPAR-γ) protein is one of the target proteins for insulin sensitivity therapy in Type 2 DM. PPAR-γ has a key role as a nuclear receptor that regulates the expression of several metabolism-related genes. This research aims to synthesize a novel benzenesulfonylurea-substituted pyridazinone derivative, namely (E)-N'-(1-(4-(3-(4-methoxyphenyl)-6-oxopyridazin-1(6H)- yl)phenyl)ethylidene)-4-methylbenzenesulfonohydrazide (8) and predicted it activity as the PPAR-γ agonist using a molecular docking approach and ADMET profiles. The compound 8 was obtained through a Schiff base condensation reaction between compound 6, p-tosyl hydrazine, and a glacial acetic acid catalyst using monowave. The purity of the compound was determined by TLC test, and melting point measurement. The structure was confirmed through FTIR, 1H-NMR, C-NMR and HRMS analysis. Molecular docking studies were carried out on the crystal structure of the human PPAR-γ Ligand Binding Domain target protein in complex with the α-aryloxyphenyl acetic acid agonist (PDB ID 1ZEO). The results of the docking show that compound 8 has a lower binding free energy than rosiglitazone (positive control) with a free energy value (S score) = -13.513 kcal/mol and -8.3089 kcal/mol, respectively. Compound 8 can form two hydrogen bonds with residues His323 and Ser289, π-π interactions with Phe363 and π-H interactions with Cys285. The interactions are similar to the interaction between the native ligand agonists α-aryloxyphenyl acetic acid and rosiglitazone with the target protein. Furthermore, compound 8 is predicted to have a moderate ADME profile. The results support that compound 8 can be developed as a PPAR-γ agonist candidate for the antidiabetic therapeutic agent.
Downloads
References
1. IDF Diabetes Atlas. International Diabetes Federation. Vol 102.; 2021. doi:10.1016/j.diabres.2021.10.013
2. Abuelizz HA, Iwana NANI, Ahmad R, Anouar EH, Marzouk M, Al-Salahi R. Synthesis, biological activity and molecular docking of new tricyclic series as α-glucosidase inhibitors. BMC Chem. 2019;13(3):1-14. doi:10.1186/s13065-019-0560-4
3. Keri RS, Patil MR, Patil SA, Budagupi S. A comprehensive review in current developments of benzothiazole-based molecules in medicinal chemistry. Eur J Med Chem. 2015;89:207-251. doi:10.1016/j.ejmech.2014.10.059
4. Janani C, Ranjitha Kumari BD. PPAR gamma gene - A review. Diabetes Metab Syndr Clin Res Rev. 2015;9(1):46-50. doi:10.1016/j.dsx.2014.09.015
5. Milligan G, Shimpukade B, Ulven T, Hudson BD. Complex pharmacology of free fatty acid receptors. Chem Rev. 2017;117(1):67-110. doi:10.1021/acs.chemrev.6b00056
6. Belete TM. A recent achievement in the discovery and development of novel targets for the treatment of type-2 diabetes mellitus. J Exp Pharmacol. 2020;12:1-15. doi:10.2147/JEP.S226113
7. Choi SS, Park J, Choi JH. Revisiting PPARγ as a target for the treatment of metabolic disorders. BMB Rep. 2014;47(11):599-608. doi:10.5483/BMBRep.2014.47.11.174
8. Park KS, Choi SH, Chung SS. Re-highlighting the action of PPARγ in treating metabolic diseases [version 1; referees: 2 approved]. F1000Research. 2018;7:1-9. doi:10.12688/f1000research.14136.1
9. Steven E. Nissen, M.D., and Kathy Wolski MPH. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. N Engl J Med. 2007;356(24). doi:10.1056/NEJMoa072761
10. Julie NL, Julie IM, Kende AI, Wilson GL. Mitochondrial dysfunction and delayed hepatotoxicity: Another lesson from troglitazone. Diabetologia. 2008;51(11):2108-2116. doi:10.1007/s00125-008-1133-6
11. Wu D, Eeda V, Undi RB, et al. A novel peroxisome proliferator-activated receptor gamma ligand improves insulin sensitivity and promotes browning of white adipose tissue in obese mice. Mol Metab. 2021;54(October):101363. doi:10.1016/j.molmet.2021.101363
12. Mourad AAE, Mourad MAE. Enhancing insulin sensitivity by dual PPARγ partial agonist, β-catenin inhibitor: Design, synthesis of new αphthalimido-o-toluoyl2-aminothiazole hybrids. Life Sci. 2020;259(June):118270. doi:10.1016/j.lfs.2020.118270
13. Jyoti Singh DS, Bansal & R. Pyridazinone: an attractive lead for anti- inflammatory and analgesic drug discovery. Future Med Chem. 2017;9(1):95-127. doi:10.2307/j.ctvnwc0d0.18
14. Khokra SL, Khan SA, Thakur P, Chowdhary D, Ahmad A, Husain A. Synthesis, Molecular Docking and Potential Antioxidant Activity of Di/Trisubstituted Pyridazinone Derivatives. J Chinese Chem Soc. 2016;63(9):739-750. doi:10.1002/jccs.201600051
15. Ahmed EM, Kassab AE, El-Malah AA, Hassan MSA. Synthesis and biological evaluation of pyridazinone derivatives as selective COX-2 inhibitors and potential anti-inflammatory agents. Eur J Med Chem. 2019;171:25-37. doi:10.1016/j.ejmech.2019.03.036
16. Khan A, Diwan A, Thabet HK, Imran M. Synthesis of novel N-substitutedphenyl-6-oxo-3-phenylpyridazine derivatives as cyclooxygenase-2 inhibitors. Drug Dev Res. 2020;81(5):573-584. doi:10.1002/ddr.21655
17. Nagle P, Pawar Y, Sonawane A, Bhosale S, More D. Docking simulation, synthesis and biological evaluation of novel pyridazinone containing thymol as potential antimicrobial agents. Med Chem Res. 2014;23(2):918-926. doi:10.1007/s00044-013-0685-2
18. Dundar Y, Kuyrukcu O, Eren G, Senol Deniz FS, Onkol T, Orhan IE. Novel pyridazinone derivatives as butyrylcholinesterase inhibitors. Bioorg Chem. 2019;92(September). doi:10.1016/j.bioorg.2019.103304
19. Yaseen R, Pushpalatha H, Reddy GB, et al. Design and synthesis of pyridazinone-substituted benzenesulphonylurea derivatives as anti-hyperglycaemic agents and inhibitors of aldose reductase – an enzyme embroiled in diabetic complications. J Enzyme Inhib Med Chem. 2016;31(6):1415-1427. doi:10.3109/14756366.2016.1142986
20. Firoozpour L, Kazemzadeh Arasi F, Toolabi M, et al. Design, synthesis and α-glucosidase inhibition study of novel pyridazin-based derivatives. Med Chem Res. 2023;32(4):713-722. doi:10.1007/s00044-023-03027-9
21. Chaudhry F, Ather AQ, Akhtar MJ, et al. Green synthesis, inhibition studies of yeast α-glucosidase and molecular docking of pyrazolylpyridazine amines. Bioorg Chem. 2017;71:170-180. doi:10.1016/j.bioorg.2017.02.003
22. Loghman Firoozpour, Setareh Moghimi, Somayeh Salarinejad, Mahsa Toolabi, Mahdi Rafsanjani, Roya Pakrad, Farzaneh Salmani, Seyed Mohammad Shokrolahi, Seyed Esmail Sadat Ebrahimi SK and AF. Synthesis, α-Glucosidase inhibitory activity and docking studies of Novel Ethyl 1,2,3-triazol-4-ylmethylthio-5,6-diphenylpyridazine-4-carboxylate derivatives. BMC Chem. 2023;17(1):4-13. doi:10.1186/s13065-023-00973-8
23. Akdağ M, Özçelik AB, Demir Y, Beydemir Ş. Design, synthesis, and aldose reductase inhibitory effect of some novel carboxylic acid derivatives bearing 2-substituted-6-aryloxo-pyridazinone moiety. J Mol Struct. 2022;1258:132675. doi:https://doi.org/10.1016/j.molstruc.2022.132675
24. Zaoui Y, Ramli Y, Tan SL, et al. Synthesis, structural characterisation and theoretical studies of a novel pyridazine derivative: Investigations of anti-inflammatory activity and inhibition of α-glucosidase. J Mol Struct. 2021;1234:130177. doi:10.1016/j.molstruc.2021.130177
25. Moghimi S, Toolabi M, Salarinejad S, et al. Design and synthesis of novel pyridazine N-aryl acetamides: In-vitro evaluation of α-glucosidase inhibition, docking, and kinetic studies. Bioorg Chem. 2020;102(June):104071. doi:10.1016/j.bioorg.2020.104071
26. Kharbanda C, Alam MS, Hamid H, et al. Antidiabetic effect of novel benzenesulfonylureas as PPAR-γ agonists and their anticancer effect. Bioorganic Med Chem Lett. 2015;25(20):4601-4605. doi:10.1016/j.bmcl.2015.08.062
27. Cruz S, Cifuentes D, Hurtado N, Román M. Síntesis de piridazin-3(2H)-onas asistida por microondas en condiciones libre de disolvente. Inf Tecnol. 2016;27(5):57-62. doi:10.4067/S0718-07642016000500007
28. Allam HA, Kamel AA, El-Daly M, George RF. Synthesis and vasodilator activity of some pyridazin-3(2H)-one based compounds. Future Med Chem. 2020;12(1):37-50. doi:10.4155/fmc-2019-0160
29. Tiryaki D, Sukuroglu M, Dogruer DS, Akkol E, Ozgen S, Sahin MF. Synthesis of some new 2,6-disubstituted-3(2H)-pyridazinone derivatives and investigation of their analgesic, anti-inflammatory and antimicrobial activities. Med Chem Res. 2013;22(6):2553-2560. doi:10.1007/s00044-012-0253-1
30. Özdemir Z, Alagöz MA, Akdemir AG, Özçelik AB, Özçelik B, Uysal M. Studies on a novel series of 3(2H)-pyridazinones: Synthesis, molecular modelling, antimicrobial activity. J Res Pharm. 2019;23(5):960-972. doi:10.35333/jrp.2019.43
31. Rahim F, Zaman K, Taha M, et al. Synthesis, in vitro alpha-glucosidase inhibitory potential of benzimidazole bearing bis-Schiff bases and their molecular docking study. Bioorg Chem. 2020;94:103394. doi:10.1016/j.bioorg.2019.103394
32. Shi GQ, Dropinski JF, McKeever BM, et al. Design and synthesis of α-aryloxyphenylacetic acid derivatives: A novel class of PPARα/γ dual agonists with potent antihyperglycemic and lipid modulating activity. J Med Chem. 2005;48(13):4457-4468. doi:10.1021/jm0502135
33. Mackerell AD, Banavali N, Foloppe N. . Published online 2001:257-265.
34. Jász Á, Rák Á, Ladjánszki I, Cserey G. Optimized GPU implementation of Merck Molecular Force Field and Universal Force Field. J Mol Struct. 2019;1188:227-233. doi:10.1016/j.molstruc.2019.04.007
35. Nazreen S, Alam MS, Hamid H, et al. Thiazolidine-2,4-diones derivatives as PPAR-γ agonists: Synthesis, molecular docking, in vitro and in vivo antidiabetic activity with hepatotoxicity risk evaluation and effect on PPAR-γ gene expression. Bioorganic Med Chem Lett. 2014;24(14):3034-3042. doi:10.1016/j.bmcl.2014.05.034
36. Lipinski CA. Rule of five in 2015 and beyond: Target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions. Adv Drug Deliv Rev. 2016;101:34-41. doi:10.1016/j.addr.2016.04.029
37. Singh SK, Valicherla GR, Bikkasani AK, et al. Elucidation of plasma protein binding, blood partitioning, permeability, CYP phenotyping and CYP inhibition studies of Withanone using validated UPLC method: An active constituent of neuroprotective herb Ashwagandha. J Ethnopharmacol. 2021;270(2021):1-25. doi:10.1016/j.jep.2021.113819
38. Van Breemen RB, Li Y. Caco-2 cell permeability assays to measure drug absorption. Expert Opin Drug Metab Toxicol. 2005;1(2):175-185. doi:https://doi.org/10.1517/17425255.1.2.175
39. Stefan David and James P Hamilton. Drug-induced liver injury. US Gastroenterol Hepatol Rev. 2010;1(6):73-80. https://europepmc.org/article/pmc/3160634
40. Andrea Iorga LD and NK. Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death, Apoptosis or Necrosis. Int J Mol Sci. 2017;18(1018):1-25. doi:https://doi.org/10.3390/ijms18051018
41. Jiang J, Pieterman CD, Ertaylan G, Peeters RLM, de Kok TMCM. The Application of Omics-Based Human Liver Platforms for Investigating the Mechanism of Drug-Induced Hepatotoxicity in Vitro. Vol 93. Springer Berlin Heidelberg; 2019. doi:10.1007/s00204-019-02585-5
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Yuni Fatisa, Elvi Yenti, Arif - Yasthophi
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
