Exploring 1,3,4-oxadiazole derivatives for hepatocellular carcinoma: synthesis, and bioactivity evaluation

Mohini Patidar; Raghvendra  Dubey; Nitin Deshmukh

doi:10.69857/joapr.v13i2.1008

Authors

Mohini Patidar Department of Pharmaceutical Chemistry, Sage University, Institute of Pharmaceutical Sciences, Indore, MP 452016, India
Raghvendra Dubey Department of Pharmaceutical Chemistry, Sage University, Institute of Pharmaceutical Sciences, Indore, MP 452016, India
Nitin Deshmukh Department of Pharmaceutical Chemistry, Mangaldeep Institute of Pharmacy, Aurangabad, Maharashtra 431001, India

DOI:

https://doi.org/10.69857/joapr.v13i2.1008

Keywords:

1,3,4-oxadiazole, Hepatocellular carcinoma, Tyrosine kinase inhibitor, EGFR, , In-vitro study

Abstract

Background: Cancer is a leading cause of death globally, with existing treatments often limited by resistance and toxicity. This necessitates the development of new, more effective anticancer therapies.

Methodology: This study used In-silico modeling with tools like Pre-ADMET and Molinspiration to evaluate the physicochemical, pharmacokinetic, and pharmacodynamic properties of substituted 1,3,4-Oxadiazole derivatives. Results and discussion: Computational studies of 1,3,4-Oxadiazole analogues showed promising drug-like properties and bioavailability. To test the inhibitory efficacy against the protein target tyrosine kinase (PDB: 1M17), 30 designed derivative compounds underwent molecular docking experiments. 10 synthesized derivatives were structurally confirmed through Mass, NMR, and IR spectrometry, ensuring their purity and identity. Molecular docking and in vitro tests identified compound S23 as a potent tyrosine kinase inhibitor, with significant anti-proliferative activity (GI50: 0.25665634) and enzyme inhibition (IC50: 1.87), highlighting its potential as a therapeutic agent. Conclusion: According to our findings, the substituted derivative might offer superior potential for developing anticancer medicine.

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References

Marina GM, Jorge AS, et al. Liver Cancer: Therapeutic Challenges and the Importance of Experimental Models. Canadian Journal of Gastroenterology and Hepatology, 8837811, 1-10 (2021) https://doi.org/10.1155/2021/8837811.

Ma Y-S, Liu J-B, Wu T-M, Fu D. New Therapeutic Options for Advanced Hepatocellular Carcinoma. Cancer Control, 27, 1-11 (2020) https://doi.org/10.1177/1073274820945975.

Qiushi Y, Xiaolong H, et al. LncRNA model predicts liver cancer drug resistance and validate in vitro experiments. Front. Cell Dev. Biol, 11, 1174183 (2023) https://doi.org/10.3389/fcell.2023.1174183.

Faisal K, Chatterjee S, Bhojani G, Sen S, et al. Seaweed polysachharide derived Bioaldehyde nanocomposite: Potential application in anticancer therapeutics. Carbohydrate Polymers, 240, 116282 (2020) https://doi.org/10.1016/j.carbpol.2020.116282.

Yan J. New knowledge of the mechanisms of Sorafenib resistance in liver cancer. Acta Pharmacologica Sinica, 38, 614–622 (2017) https://doi.org/10.1038/aps.2017.5.

Rathod S. Recent court orders in patent suits on limits of Bolar exemption: Shrinking space for pharmaceutical generic companies in India?. Journal of generic medicines, 18(3), 1-10 (2021) https://doi.org/10.1177/17411343211038999.

Zuhair A, Sarah AH, et al. Studying the anti-cancer activity of Resveratrol 1,3,4-Thiadiazol derivatives. Research J. Pharm. and Tech., 15(10), 4377-1 (2022) https://doi.org/10.52711/0974-360X.2022.00734.

Zahraa TK, Entesar OAT. Synthesis, Identification, Theoretical Study and effect of 1,3,4-Oxadiazole Compounds Substituted on Creatinine ring on the activity of some Transfers Enzymes. Research J. Pharm. and Tech., 12(8), 3581-3588 (2019) https://doi.org/10.5958/0974-360X.2019.00611.5.

Bang J, Jun M, Lee S, Moon H, Ro SW. Targeting EGFR/PI3K/AKT/mTOR signaling in hepatocellular carcinoma. Pharmaceutics, 15(8), 2130 (2023) https://doi.org/10.3390/pharmaceutics15082130.

Pavlo VZ, Vadym VK, Teslenko N, et al. In Silico Prediction and Molecular Docking Studies of N-Amidoalkylated Derivatives of 1,3,4-Oxadiazole as COX-1 and COX-2 Potential Inhibitors. Research J. Pharm. and Tech., 10(11), 3957-3963 (2017) https://doi.org/10.5958/0974-360X.2017.00718.1.

Stamos J, Sliwkowski M, Eigenbrot C. Structure of the Epidermal Growth Factor Receptor Kinase DomainAlone and in Complex with a 4-Anilinoquinazoline Inhibitor. The journal of biological chemistry, 277, 46265–4272 (2002) https://doi.org/10.1074/jbc.M207135200.

Bala S, Kamboj S, Anu K, Saini V, Deo N. 1,3,4-Oxadiazole Derivatives: Synthesis, Characterization, Antimicrobial Potential, and Computational Studies. Biomed Res Int., 172791, 18(2014) https://doi.org/10.1155/2014/172791

Singhai A, Gupta MK. Synthesis and Characterization of 1,3,4-Oxadiazole Derivatives as Potential Anti-inflammatory and Analgesic agents. Research J. Pharm. and Tech.,13(12), 5898-5902 (2020) https://doi.org/10.5958/0974-360X.2020.01029.X.

Pavlo VZ, Ihor OP, Vadym VK, Oxana VO, Aleksandr VK. Molecular Docking Studies of N-(((5-Aryl-1,3,4-oxadiazol-2-yl)amino)methyl)- and N-(2,2,2-Trichloro-1-((5-aryl-1,3,4-oxadiazol-2-yl)amino)ethyl)carboxamides as Potential Inhibitors of GSK-3β. Research J. Pharm. and Tech., 12(2), 523-530 (2019) https://doi.org/10.5958/0974-360X.2019.00092.1.

Camelia E. Synthesis and Anticancer Evaluation of New1,3,4-Oxadiazole Derivatives. Pharmaceuticals, 14, 438 (2021) https://doi.org/10.3390/ph14050438.

Ragab F, Abou-Seri S, Salah A, et al. Design, synthesis and anticancer activity of new monastrol analogues bearing 1,3,4-oxadiazole moiety. European Journal of Medicinal Chemistry, 17, 30472-510 (2017) https://doi.org/1016/j.ejmech.2017.06.026.

Bajaj S, Roy P, Singh J. Synthesis, Thymidine Phosphorylase inhibitory and computational study of novel 1,3,4-oxadiazole-2-thionederivatives as potential anticancer agents. Computational Biology and Chemistry, 18, 1-36 (2018) https://doi.org/10.1016/j.compbiolchem.2018.05.013.

Chakrabhavi D. Noval 1,3,4-oxadiazole induce anticancer activity by targeting NF-kB in hepatocellular carcinoma cell, Front. Oncol, 8, 42(2018) https://doi.org/10.3389/fonc.2018.00042.

Stamos J, Sliwkowski M, Eigenbrot C. Structure of the Epidermal Growth Factor Receptor Kinase Domain Alone and in Complex with a 4-Anilinoquinazoline Inhibitor. The journal of biological chemistry, 277, 46265–46272 (2002) https://doi.org/10.1074/jbc.M207135200.

Puttaswamy N, Malojiao V, Yasser H, et al. Synthesis and amelioration of inflammatory paw edema by novel benzophenone appended oxadiazole derivatives by exhibiting cyclooxygenase-2 antagonist activity. Biomedicine & Pharmacotherapy, 103, 1446–1455 (2018) https://doi.org/10.1016/j.biopha.2018.04.167.

Yadav N, Kumar P, Chhikara A, Madhu, et al. Development of 1,3,4-oxadiazole thione based novel anticancer agents: Design, synthesis and in-vitro studies. Biomedicine & Pharmacotherapy, 95, 721–730 (2017) http://dx.doi.org/10.1016/j.biopha.2017.08.110.

Pidugu V, SastryYarla N, Pedada S, Kalle A, Satya K. Design and synthesis of novel HDAC8 inhibitory 2,5-disubstituted-1,3,4-oxadiazoles containing glycine and alanine hybrids with anticancer activity. Bioorganic & Medicinal Chemistry, 24, 5611–5617 (2016) http://dx.doi.org/10.1016/j.bmc.2016.09.022.

Kumar D, Sundaree S, Johnson EO, Shah K. An efficient synthesis and biological study of novel indolyl- 1, 3, 4-oxadiazoles as potent anticancer agents. Bioorg. Med. Chem. Lett., 19 (15), 4492–4494 (2009) http://dx.doi.org/10.1016/j.bmcl.2009.03.172.

Abdel-Aziz MA, Metwally K, Gamal-Eldeen AM, et al. 1,3,4-oxadiazole-2-thione derivatives; novel approach for anticancer and tubulin polymerization inhibitory activities. Anti-Cancer Agents Med. Chem., 16(2), 269–277 (2016) 10.2174/1871520615666150907093855.

Vichai V and Kirtikara K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nature Protocols, 1(3), 1112-6 (2006) http://dx.doi.org/10.1038/nprot.2006.179.

Kode J, Kovvuri J, Nagaraju B, et al. Synthesis, biological evaluation and molecular docking analysis of phenstatin based indole linked chalcones as anticancer agents and tubulin polymerization inhibitors. Bioorganic Chemistry, 105, 104447 (2020) https://doi.org/10.1016/j.bioorg.2020.104447.

Skehan P, Storeng R, Scudiero D, et al. New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst., 82, 1107-1112 (1990).

Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods, 65 (1-2), 55–63(1983) 10.1016/0022-1759(83)90303-4.

Ahmad A, Varshney H, Rauf A, A Sherwani, M Owais. Synthesis and anticancer activity of long chain substituted 1, 3, 4-oxadiazol-2-thione, 1, 2, 4-triazol-3-thione and 1, 2, 4-triazolo 3,4-b-1, 3, 4-thiadiazine derivatives. Arab. J. Chem., 10 (2), S3347–S3357 (2017) https://doi.org/10.1016/j.arabjc.2014.01.015.

Gudipati R, Anreddy RNR, Manda S. Synthesis, characterization and anticancer activity of certain 3-{4-(5-mercapto-1, 3, 4-oxadiazole-2-yl) phenylimino} indolin-2-one derivatives, Saudi Pharm. J.,19 (3), 153–158 (2011) https://doi.org/10.1016/j.jsps.2011.03.002.

Qinlian J, Lei Bi, Yidan R, Song S, et al. Advances in studies of tyrosine kinase inhibitors and their acquired resistance. Molecular Cancer, 17, 36 (2018) https://doi.org/10.1186/s12943-018-0801-5.

Labots M, Gotink K J, Dekker H, et al. Evaluation of a tyrosine kinase peptide microarray for tyrosine. kinase inhibitor therapy selection in cancer. Experimental & Molecular Medicine, 48, 279 (2016) https://doi.org/10.1038/emm.2016.114.

Josephine MA, Naichen Y, Xiaobo W, Xiao Xu, et al. Label-Free and Real-Time Cell-Based Kinase Assay for Screening Selective and Potent Receptor Tyrosine Kinase Inhibitors Using Microelectronic Sensor Array. Journal of Biomolecular Screening, 11(6), 10 (2006) https://doi.org/10.1177/1087057106289334.