Synthesis and Evaluation of Mannich Base Derivatives of Hexyl Ferulate as Antibacterial and Antioxidant Agents
Downloads
Antimicrobial resistance (AMR) has become a critical global health issue, particularly in developing countries where bacterial infections remain prevalent and treatment options are increasingly limited. The rising resistance of pathogens such as Staphylococcus aureus and Escherichia coli highlights the urgent need for new antibacterial agents with improved efficacy. In addition, oxidative stress contributes to cellular damage, making compounds with dual antioxidant and antibacterial properties highly valuable. This study aims to synthesize and evaluate Mannich base derivatives of hexyl ferulate as potential antibacterial and antioxidant agents. The research employed an experimental laboratory approach, including the synthesis of ferulic acid derivatives through esterification and Mannich reactions, followed by structural characterization using spectroscopic methods. Antioxidant activity was assessed using DPPH and FRAP assays, while antibacterial activity was evaluated through agar diffusion and dilution methods. The results showed that Mannich base derivatives exhibited significantly enhanced antioxidant activity, with lower IC₅₀ and EC₅₀ values compared to ferulic acid and hexyl ferulate. In antibacterial testing, the derivatives demonstrated stronger inhibition against both Gram-positive and Gram-negative bacteria, with certain compounds showing superior activity. These findings indicate that structural modification through Mannich substitution effectively improves biological activity. In conclusion, Mannich base derivatives of hexyl ferulate have strong potential as lead compounds for developing new antibacterial and antioxidant agents to address AMR challenges.
Alifah, L. H. N., Chandra, H. M., Rafael, R., Jatmika, C., & Hayun, H. (2025). Synthesis and bioactivity study of Mannich base derivatives of ferulic acid as a tyrosinase inhibitor and antioxidant. Egyptian Journal of Chemistry, 68(2), 39–46. https://doi.org/10.21608/ejchem.2024.281898.9561
Balouiri, M., Sadiki, M., & Ibnsouda, S. K. (2016). Methods for in vitro evaluating antimicrobial activity: A review. Journal of Pharmaceutical Analysis, 6(2), 71–79. https://doi.org/10.1016/j.jpha.2015.11.005
Bobunja-Sonje, M., Tomić, S., Pavlović, D. M., Šegvić Klarić, M., & Blažeković, B. (2020). Challenges to antimicrobial susceptibility testing of plant-derived polyphenolic compounds. Arhiv za Higijenu Rada i Toksikologiju, 71(4), 300–311. https://doi.org/10.2478/aiht-2020-71-3396
Cloutier, C. A., Bisaillon, A., Morand, M., & Legault, J. (2018). QSAR-based molecular signatures of prenylated (iso)flavonoids underlying antimicrobial potency against and membrane disruption in Gram-positive and Gram-negative bacteria. Scientific Reports, 8, 9267. https://doi.org/10.1038/s41598-018-27545-4
Dachriyanus. (2014). Analisis struktur senyawa organik secara spektroskopi. Padang: Lembaga Pengembangan Teknologi Informasi dan Komunikasi (LPTIK), Universitas Andalas.
Dua, T., Mangal, S., Akshita, G., Harshdeep, A., Atri, A. K., Sharma, P., Harjai, K., & Singh, V. (2023). Novel vanillin‐based hybrids inhibit quorum sensing and silence phenotypical expressions in Pseudomonas aeruginosa. Drug Development Research, 84(1), 45–61. https://doi.org/10.1002/ddr.22011
Halpani, C. G., & Mishra, S. (2024). Design, synthesis, and characterization of ferulic acid and p-coumaric acid amide derivatives as antibacterial/antioxidant agents. Pharmaceutical Sciences Advances, 2, 100023. https://doi.org/10.1016/j.pscia.2023.100023
Hayun, H., Gavrila, I., Silviana, S., Siahaan, A. E. K., Vonna, R. F., & Latifah, M. I. (2020). Synthesis and antioxidant activity study of new Mannich bases derived from vanillic acid. Rasayan Journal of Chemistry, 13(1), 131–138. https://doi.org/10.31788/RJC.2020.1315300
Institute for Health Metrics and Evaluation (IHME). (2019). Antimicrobial resistance in Indonesia: Deaths attributable and associated with AMR. Retrieved from https://www.healthdata.org
Kalinowska, M., Piekut, J., Bruss, A., Follet, C., Sienkiewicz-Gromiuk, J., Świsłocka, R., Rzączyńska, Z., & Lewandowski, W. (2014). Spectroscopic (FT-IR, FT-Raman, ¹H, ¹³C NMR, UV/VIS), thermogravimetric and antimicrobial studies of Ca(II), Mn(II), Cu(II), Zn(II) and Cd(II) complexes of ferulic acid. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 122, 631–638. https://doi.org/10.1016/j.saa.2013.11.089
Kementerian Kesehatan Republik Indonesia. (2021). Resistensi antimikroba ancaman kesehatan paling mendesak, strategi one health perlu digencarkan. Retrieved from https://kemkes.go.id/id/resistensi-antimikroba-ancaman-kesehatan-paling-mendesak-strategi-one-health-perlu-digencarkan
Khac Vu, T. (2014). Synthesis of novel ferulic acid–based Mannich bases. Vietnam Journal of Chemistry, 52(2), 201–219.
Murray, C. J., Ikuta, K. S., Sharara, F., Swetschinski, L., Robles Aguilar, G., Gray, A., Han, C., Bisignano, C., Rao, P., Wool, E., Johnson, S. C., Browne, A. J., Chipeta, M. G., Fell, F., Hackett, S., Haines-Woodhouse, G., Kashef Hamadani, B. H., Kumaran, E. A. P., McManigal, B., … Naghavi, M. (2022). Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis. The Lancet, 399(10325), 629–655. https://doi.org/10.1016/S0140-6736(21)02724-0
Plech, T., Wujec, M., Siwek, A., Kosikowska, U., & Malm, A. (2013). Microbiologically active Mannich bases derived from 1,2,4-triazoles: The effect of C-5 substituent on antibacterial activity. Medicinal Chemistry Research, 22(6), 2531–2537. https://doi.org/10.1007/s00044-012-0248-y
Rani, U., Kumar, M., Grewal, S., Kaushik, S., & Thakur, R. (2024). Novel synthesis of trans-ferulic acid loaded tragacanth-chitosan nanoformulations and evaluation of their biological activities. European Journal of Medicinal Chemistry Reports, 11, 100165. https://doi.org/10.1016/j.ejmcr.2024.100165
Sajjadi, S. E., Shokoohinia, Y., & Moayedi, N.-S. (2012). Isolation and identification of ferulic acid from aerial parts of Kelussia odoratissima Mozaff. Jundishapur Journal of Natural Pharmaceutical Products, 7(4), 159–162. https://doi.org/10.5812/jjnpp.7705
Schijndel, J., Canalle, L. A., Molendijk, D., & Meuldijk, J. (2017). The green Knoevenagel condensation: Solvent-free condensation of benzaldehydes. Green Chemistry Letters and Reviews, 10(4), 404–411. https://doi.org/10.1080/17518253.2017.1391881
Silverstein, R. M., Webster, F. X., & Kiemle, D. J. (1998). Spectrometric identification of organic compounds (D. Brennan, Ed.; 7th ed.). California: John Wiley & Sons, Inc.
Song, W., Xin, J., Yu, C., Xia, C., & Pan, Y. (2023). Alkyl ferulic acid esters: Evaluating their structure and antibacterial properties. Frontiers in Microbiology, 14, 1135308. https://doi.org/10.3389/fmicb.2023.1135308
Tokalı, F. S., Taslimi, P., Demircioğlu, İ. H., Şendil, K., Tuzun, B., & Gülçin, İ. (2021). Novel phenolic Mannich base derivatives: Synthesis, bioactivity, molecular docking, and ADME-Tox studies. Journal of the Iranian Chemical Society, 18(11), 2767–2782. https://doi.org/10.1007/s13738-021-02331-8
Uddin, T. M., Chakraborty, A. J., Khusro, A., Zidan, B. R. M., Mitra, S., Emran, T. B., Dhama, K., Ripon, M. K. H., Gajdács, M., Sahibzada, M. U. K., Hossain, M. J., & Koirala, N. (2021). Antibiotic resistance in microbes: History, mechanisms, therapeutic strategies and future prospects. Journal of Infection and Public Health, 14(12), 1750–1766. https://doi.org/10.1016/j.jiph.2021.10.020
Untung, J., Iskandarsyah, I., & Hayun, H. (2017). 2-[(2,6-Dimethylmorpholin-4-yl)methyl]-4-[(E)-2-{3-[(E)-2-{3-[(2,6-dimethylmorpholin-4-yl)methyl]-4-hydroxy-5-methoxyphenyl}ethenyl]-1H-pyrazol-5-yl}ethenyl]-6-methoxyphenol. Molbank, 2017(M949). https://doi.org/10.3390/M949
Walsh, T. R., Gales, A. C., Laxminarayan, R., & Dodd, P. C. (2023). Antimicrobial resistance: Addressing a global threat to humanity. PLoS Medicine, 20(7), e1004264. https://doi.org/10.1371/journal.pmed.1004264
Wulandari, R. P., Rachman, F., & Setiawan, H. (2023). In silico study of secondary metabolite compounds in parsley (Petroselinum crispum) as a drug therapy for blood cancer (myeloproliferative neoplasm (MPN)) targeting JAK-2. Indonesian Journal of Chemical Science, 12(2).
Zheng, M., Liu, Y., Zhang, G., Yang, Z., Xu, W., & Chen, Q. (2024). The antioxidant properties, metabolism, application, and mechanism of ferulic acid in medicine, food, cosmetics, livestock, and poultry. Antioxidants, 13(7), 853. https://doi.org/10.3390/antiox13070853
Copyright (c) 2026 Kadek Devi Arum Savitri, Hayun Hayun, Herman Suryadi
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
