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  2. Jurnal Kimia VALENSI, Volume 11, No. 1, May 2025 (in press)
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A Novel Benzenesulfonylurea-Substituted Pyridazinone Derivative with Antidiabetic Effect as the Peroxisome Proliferator-activated Receptor (PPAR-γ) Agonist

Yuni Fatisa, Arif Yasthophi, Elviyenti Elviyenti, Ihsan Ikhtiaruddin, Neni Frimayanti, Hilwan Yuda Teruna, Jasril Jasril

Abstract


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.

Keywords


ADMET; schiff base condensation; molecular docking; PPAR-γ agonist

References


IDF Diabetes Atlas. International Diabetes Federation. Vol 102.; 2021. doi:10.1016/j.diabres.2021.10.013

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Mackerell AD, Banavali N, Foloppe N. . Published online 2001:257-265.

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

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

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

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

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

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

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

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




DOI: 10.15408/jkv.v11i1.42187

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