Synthesis and In Silico Study of 5’-Chloro-2’,4-Dihydroxy-3-Methoxychalcone as Potential Inhibitors of Estrogen Receptors Alpha

Authors

  • Rizka Amalia Putri Department of Chemistry Education, Faculty of Teacher Training and Education, Universitas Mulawarman, Jl. Muara Pahu, Samarinda, Indonesia 75123, Indonesia
  • Aisyah Zahra Nurramadhani Department of Chemistry Education, Faculty of Teacher Training and Education, Universitas Mulawarman, Jl. Muara Pahu, Samarinda, Indonesia 75123, Indonesia
  • Agustina Amalia Islami Department of Chemistry Education, Faculty of Teacher Training and Education, Universitas Mulawarman, Jl. Muara Pahu, Samarinda, Indonesia 75123, Indonesia
  • Auriel Wafiq Tristania Department of Chemistry Education, Faculty of Teacher Training and Education, Universitas Mulawarman, Jl. Muara Pahu, Samarinda, Indonesia 75123, Indonesia
  • Isma Aulia Department of Chemistry Education, Faculty of Teacher Training and Education, Universitas Mulawarman, Jl. Muara Pahu, Samarinda, Indonesia 75123, Indonesia
  • Harra Ismi Farah Department of Pharmaceutical Science, Faculty of Pharmacy, Universitas Mulawarman, Jl. Penajam, Samarinda, Indonesia 75123, Indonesia
  • Hanggara Arifian Department of Pharmaceutical Science, Faculty of Pharmacy, Universitas Mulawarman, Jl. Penajam, Samarinda, Indonesia 75123, Indonesia
  • Agung Rahmadani Department of Chemistry Education, Faculty of Teacher Training and Education, Universitas Mulawarman, Jl. Muara Pahu, Samarinda, Indonesia 75123, Indonesia http://orcid.org/0009-0001-2301-5892

DOI:

https://doi.org/10.33394/hjkk.v13i2.15546

Keywords:

ADME, chalcone, molecular docking, receptor erα, synthesis

Abstract

The high prevalence of breast cancer necessitates the discovery of new, more effective, and safer anticancer compounds. Chalcone, a flavonoid with promising anticancer activity, is limited by poor bioavailability and rare natural occurrence. In this study, a novel chalcone derivative, 5'-chloro-2',4-dihydroxy-3-methoxychalcone, was synthesized on a laboratory scale via Claisen-Schmidt condensation using 5-chloro-2-hydroxyacetophenone and 4-hydroxy-3-methoxybenzaldehyde as starting materials. The structure of the synthesized compound was confirmed by mass spectrometry and NMR analysis. Pharmacokinetic and toxicity profiles were predicted in silico using SwissADME, while molecular docking simulations with the ERα receptor were performed using AutoDockTools. The compound was obtained as a yellow solid with a yield of 70.15%, showed favorable ADME properties based on Lipinski’s and Veber’s rules, and demonstrated a binding energy of -7.82 kcal/mol to the ERα receptor, indicating potential as an anticancer agent. The novelty of this research is the successfully synthesized and characterized of this specific chalcone, which is structurally different from previously reported analogs. These findings enrich the diversity of chalcone derivatives and provide a new basis for developing synthesis-based drug candidates targeting breast cancer.

References

Ahsan, R., Paul, S., Alam, M. S., & Rahman, A. F. M. M. (2025). Synthesis, biological properties, in silico ADME, molecular docking studies, and FMO analysis of chalcone derivatives as promising antioxidant and antimicrobial agents. ACS Omega, 10(5), 4367–4387. https://doi.org/10.1021/acsomega.4c06897.

Aldaghi, L., Rad, A., Arab, A., Kasaian, J., Iranshasi, M., Sadr, A. S., & Soltani, F. (2016). In Silico and In Vitro Evaluation of Cytotoxic Activities of Farnesiferol C and Microlobin on MCF-7. Hela and KYSE Cell Lines. Drug. Res. 66(10): 532-538. https://doi.org/10.1055/s-0042-111200.

Anusionwu C. G., Fonkui T. Y., Oselusi S. O., Egieyeh S. A., Aderibigbe B. A., and Mbianda X. Y. (2024). Ferrocene-bisphosphonates Hybrid Drug Molecules: In Vitro Antibacterial and Antifungal, In Silico ADME, Drug-likeness, and Molecular Docking Studies. Results in Chemistry, 7(101278): 1-13. https://doi.org/10.1016/j.rechem.2023.101278.

Baroroh, U., Muscipa, Z. S., Destiarani, W., Rahmatullah, F. G., & Yusuf, M. (2023). Molecular Interaction Analysis and Visualization of Protein-Ligand Docking Using Biovia Discovery Studio Visualizer. Indonesian Journal of Computational Biology. 2(1): 22-30. https://doi.org/10.24198/ijcb.v2i1.46322.

Bender, O., Celik, I., Dogan, R., Atalay, A., Shoman, M. E., Ali, T. F. S., Beshr, E. A. M., Mohamed, M., Alaaeldin, E., Shawky, A. M., Awad, E. M., Ahmed, A.-S. F., Younes, K. M., Ansari, M., & Anwar, S. (2023). Vanillin-based indolin-2-one derivative bearing a pyridyl moiety as a promising anti-breast cancer agent via anti-estrogenic activity. ACS Omega, 8(7), 6968–6981. https://doi.org/10.1021/acsomega.2c0779.

Chlebek, J., KorábeÄný, J., Doležal, R., Å tÄ›pánková, S., Pérez, D. I., Hošťálková, A., Opletal, L., Cahlíková, L., Macáková, K., KuÄera, T., Hrabinová, M., and Jun, D. (2019). “In Vitro and In Silico Acetylcholinesterase Inhibitory Activity of Thalictricavine and Canadine and Their Predicted Penetration across the Blood-Brain Barrier. Molecules, 24(7): 1340. doi: https://doi.org/10.3390/molecules24071340.

D.Ranjith, C. Ravikumar. (2019). SwissADME Predictions of Pharmacokinetics and Drug-likeness Properties of Small Molecules Present in Ipomoea mauritiana Jacq. J Pharmacogn. Phytochem. 8(5): 2063–2073.

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): 42717. https://doi.org/10.1038/srep42717.

Dona, R., Frimayanti, N., Ikhtiarudin, I., Iskandar, B., Maulana, F., & Silalahi, N. T. (2019). Studi In Silico, Sintesis, dan Uji Sitotoksik Senyawa P-Metoksi Kalkon Terhadap Sel Kanker Payudara MCF-7. Jurnal Sains Farmasi dan Klinis, 6(3): 243-249. http://dx.doi.org/10.25077/jsfk.6.3.243-249.

Ekanayake, U. G. M., Weerathunga, H., Weerasinghe, J., Waclawik, E. R., Sun, Z., MacLeod, J. M., O’Mullane, A. P., & Ostrikov, K. (2022). Sustainable ClaisenSchmidt Chalcone Synthesis Catalysed by Plasma-Recovered MgO Nanosheets from Seawater. Sustainable Materials and Technologies, 32(394): 1-8. https://doi.org/10.1016/j.susmat.2022.e00394.

Forli, S., Huey, R., Pique, M. E., Sanner, M. F., Goodsell, D. S., & Olson, A. J. (2016). Computational Protein–Ligand Docking and Virtual Drug Screening with the AutoDock Suite. Natureprotocols, 11(5): 905-919. https://doi.org/10.1038/nprot.2016.051.

Haque, M., Beg, M. A., Singh, V., Abd Elneam, A. I., Arshad, M., & Thakur, S. C. (2023). Design, synthesis, molecular docking, anticancer, antiproliferative, and antioxidant studies of novel chalcones derivatives. Russian Journal of Bioorganic Chemistry, 49(4), 567–582. https://doi.org/10.1134/S1068162023040118.

Jumina, J., Styaningrum, R. W., Siswanta, D., Triono, S., Priastomo, Y., Harizal, H., Sholikhah, E. N., & Zulkarnain, A. K. (2019). Synthesis and Preliminary Evaluation of Several Chalcone Derivatives as Broad-spectrum UV Protectors with Intrinsic Antioxidant Activity. Chemistry Journal of Moldova, 14(2), 90–96. http://dx.doi.org/10.19261/cjm.2019.624.

Meilinda, E. R., Rahmadani, A., Hajrah., & Rijai, L. (2018). Pharmaceutical Potential of 2’,4’-Dichloro-4-Hydroxy-3 Methoxychalcone Synthesized From Vaniline. Journal Tropical Pharmacy and Chemistry, 4(4). 168-174. https://doi.org/10.25026/jtpc.v4i4.181.

Mulyani, M., Farah. H.I., Rusli, R., & Rahmadani, A. (2021). Synthesis and Toxicity Test of 2’-Hydroxy-5’Chloro-3,4-Dymethoxychalcone. AIP Publishing, 2360, 050023. https://doi.org/10.1063/5.0059535.

Matsjeh, S., Swasono, R. T., Anwar, C., Solikhah, E. N., & Lestari, E. (2017). Synthesis Of 2’,4-Dihydroxy-3-Methoxychalcone And 2’,4’,4-Trihydroxy-3-Methoxychalcone As A Candidate Anticancer Against Cervical (Widr), Colon (Hela), And Breast (T47d) Cancer Cell Lines In Vitro. AIP Conf. Proc, 1823, 020048. https://doi.org/10.1063/1.4978121.

Ndombera, F. T., Maiyoh, G. K. K., & Vivian, C. T. (2019). Pharmacokinetic, Physicochemical and Medicinal Properties of N-Glycoside Anti-Cancer Agent more Potent than 2-Deoxy-D-Glucose in Lung Cancer Cells. Cancer Sci Res Open Access 6(1): 1-8. https://doi.org/10.17265/2328-2150/2019.04.003.

Nematollahi, M. H., Mehrabani, M., Hozhabri, Y., Mirtajaddini, M., & Iravani, S. (2023). Antiviral and Antimicrobial Applications of Chalcones and Their Derivatives: From Nature to Greener Synthesis. Heliyon, 9, e20428. https://doi.org/10.1016/j.heliyon.2023.e20428.

Pratama, M. R. F., & Siswandono. (2020). Number of runs variations on AutoDock 4 do not have a significant effect on RMSD from docking results. Pharmacy & Pharmacology, 8(6), 476–480. https://doi.org/10.19163/2307-9266-2020-8-6-476-480.

Pires, D. E. V., Blundell, T. L., & Ascher, D. B. (2015). pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. Journal of Medicinal Chemistry, 58(9), 4066–4072. https://doi.org/10.1021/acs.jmedchem.5b00104.

Rahmawati, R., & Sofia, B. F. D. (2022). Katalis Heterogen Allumina pada Sintesis Kalkon dari Vanilin. Jurnal Kimia dan Pendidikan Kimia, 4(1): 79-85. https://doi.org/10.20414/spin.v4i1.5121.

Rana, M., Faizan, M. I., Dar, S. H., Ahmad, T., & Rahisuddin. (2022). Design and synthesis of carbothioamide/carboxamide-based pyrazoline analogs as potential anticancer agents: Apoptosis, molecular docking, ADME assay, and DNA binding studies. ACS Omega, 7(26), 22639–22656. https://doi.org/10.1021/acsomega.2c02033.

Safitri, W. N., Maulidya, V., Rahmadani, A., & Rijai, L. (2021). Synthesis and biological activity of chlorochalcone derivative. AIP Conference Proceedings, 2360(1), 050036. https://doi.org/10.1063/5.0059499.

Sagitasa, S., Elizabeth, K., Sulaiman, L, I., Rafasafly, A., Syafra, D. W., Kristande, A., & Muchtardi, M. (2021). Studi In Silico Senyawa Aktif Daun Singawalang (Petiveria alliacea) Sebagai Penurun Kadar Glukosa Darah Untuk Pengobatan Penyakit Diabetes Melitus Tipe-2. Chimica et Natura Acta, 9(2): 58–66. https://doi.org/10.24198/cna.v9.n2.34083.

Sangpheak, K., Tabtimmai. L., Seetaha, S., Rungnim, C., Chavasiri, W., Wolschann, P., Choowongkomon, K., & Rungrotmongkol, T. (2019). Biological Evaluation and Molecular Dynamics Simulation of Chalcone Derivates as Epidermal Growth Factor-Tyrosine Kinase Inhibitors. Molecules, 24(6): 1092. https://doi.org/10.3390/molecules24061092.

Shidiq, N., Rahmadani, A., Wijaya, V., & Rijai, L. (2018). Sintesis Senyawa Turunan Flavanon dan Uji Bioaktivitas Senyawa Kalkon sebagai Senyawa Antara dalam Sintesis Flavanon. Proceeding of the 8th Mulawarman Pharmaceuticals Conferences, 8(1): 68–74. http://dx.doi.org/10.25026/mpc.v8i1.305.

Shtaiwi, A., Adnan, R., Khairuddean, M., & Khan, S. U. 2019. Computational investigations of the binding mechanism of novel benzophenone imine inhibitors for the treatment of breast cancer. RSC Adv, 9 : 35401-35416. https://doi.org/10.1039/C9RA04759J.

Shylaja, R., Loganathan, C., Kabilan, S., Vijayakumar, T., & Meganathan, C. (2021). Synthesis and evaluation of the antagonistic activity of 3-acetyl-2H-benzo[g]chromen-2-one against mutant Y537S estrogen receptor alpha via E-Pharmacophore modeling, molecular docking, molecular dynamics, and in-vitro cytotoxicity studies. Journal of Molecular Structure, 1224: 129-289. https://doi.org/10.1016/j.molstruc.2020.129289.

Singh, N., Kumar, N., Rathee, G., Sood, D., Singh, A., Tomar, V., Dass, S. K., & Chandra, R. (2020). Privileged Scaffold Chalcone: Synthesis, Characterization, and Its Mechanistic Interaction Studies with BSA Employing Spectroscopic and Chemoinformatics Approaches. ACS Omega, 5(1): 2267-2279. https://doi.org/10.1021/acsomega.9b03479.

Susanti, E., & Mulyani. (2022). Green Synthesis, Characterization, and, Antibacterial Activity of Methoxy Chalcones. Rasayan Journal of Chemistry, 15(4): 2459-2465. http://doi.org/10.31788/RJC.2022.1546957.

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Published

2025-05-15

How to Cite

Putri, R. A., Nurramadhani, A. Z., Islami, A. A., Tristania, A. W., Aulia, I., Farah, H. I., … Rahmadani, A. (2025). Synthesis and In Silico Study of 5’-Chloro-2’,4-Dihydroxy-3-Methoxychalcone as Potential Inhibitors of Estrogen Receptors Alpha. Hydrogen: Jurnal Kependidikan Kimia, 13(2), 405–415. https://doi.org/10.33394/hjkk.v13i2.15546

Issue

Vol. 13 No. 2 (2025): April 2025

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