Rapid and Controlled: Microflow Reactor-Assisted Synthesis of Cinnamaldehyde and Ethyl Cinnamate along with Their Cytotoxic Activity Against Several Cell Lines
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Submitted
15 December 2025
Published
30 June 2026
Keywords:
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Microflow Reactor, Cinnamaldehyde Synthesis, Ethyl Cinnamate, Green Chemistry, Cytotoxic Activity
Abstract
Cinnamaldehyde is a major aromatic compound utilized in the pharmaceutical industry due to its diverse biological activities, including anticancer potential. This study aims to develop a rapid and controlled synthesis method for cinnamaldehyde and ethyl cinnamate using microflow reactor technology, followed by structural elucidation and cytotoxic evaluation against HeLa, MCF-7, and T47D cancer cell lines. The synthesis of cinnamaldehyde was performed via aldol condensation of benzaldehyde and acetaldehyde (1.3:1 molar ratio) at 70°C, while ethyl cinnamate was synthesized through a two-step process involving Pinnick oxidation and Fischer esterification. The results demonstrated that microflow synthesis achieved a cinnamaldehyde yield of 52% with high purity (100% based on HPLC relative area), and ethyl cinnamate with 99% purity. In cytotoxic assays, synthesized cinnamaldehyde exhibited moderate activity, most notably against HeLa cells with an IC₅₀ of 95 µg/mL, whereas ethyl cinnamate showed lower potency (IC₅₀ > 200 µg/mL). Although the synthesized compounds were less potent than the standard cinnamaldehyde (IC₅₀ 1.56 µg/mL) and Doxorubicin control, this study confirms that microflow reactor technology is a highly effective and time-efficient method for producing high-purity cinnamate derivatives.
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References
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25. Wang S, He M, Li L, Liang Z, Zou Z, Tao A. Cell-in-Cell Death Is Not Restricted by Caspase-3 Deficiency in MCF-7 Cells. J Breast Cancer. 2016;19(3):231-41. DOI: 10.4048/jbc.2016.19.3.231; PMID: 27721872; PMCID: PMC5053307.
26. Theodossiou TA, Olsen CE, Jonsson M, Kubin A, Hothersall JS, Berg K. The diverse roles of glutathione-associated cell resistance against hypericin photodynamic therapy. Redox Biol. 2017;12:191-7. DOI: 10.1016/j.redox.2017.02.018; PMID: 28254657; PMCID: PMC5333531.
2. Zhang G, Li T, Liu J, Wu X, Yi H. Cinnamaldehyde-Contained Polymers and Their Biomedical Applications. Polymers. 2023;15(6):1517. DOI: 10.3390/polym15061517; PMID: 36987298; PMCID: PMC10051895.
3. Guo J, Yan S, Jiang X, Su Z, Zhang F, Xie J, et al. Advances in pharmacological effects and mechanism of action of cinnamaldehyde. Front Pharmacol. 2024;15:1365949. DOI: 10.3389/fphar.2024.1365949; PMID: 38903995; PMCID: PMC11187351.
4. Handayani A, Lailaty IQ, Rosyidah A, Sari DRT, Yunarto N, Suherman D. Indonesian Cinnamon (Cinnamomum burmanni (Nees & T. Nees) Blume) as Promising Medicinal Resources: A Review. J Sylva Lestari. 2024;12(3):610-33. DOI: 10.23960/jsl.v12i3.929.
5. Fanelli F, Parisi G, Degennaro L, Luisi R. Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis. Beilstein J Org Chem. 2017;13:520-42. DOI: 10.3762/bjoc.13.51; PMID: 28405232; PMCID: PMC5372749.
6. Capaldo L, Wen Z, Noël T. A field guide to flow chemistry for synthetic organic chemists. Chem Sci. 2023;14(16):4230-47. DOI: 10.1039/d3sc00992k; PMID: 37123197; PMCID: PMC10132167.
7. Jung J, Kaiser L, Deigner HP, Schmidt MS. Continuous synthesis of bromoalkyl glycosides by Fischer glycosylation in a microreactor. J Flow Chem. 2022;12:9-15. DOI: 10.1007/s41981-021-00202-0.
8. Richmond HH, inventor. Uniroyal Inc, assigne. Preparation of cinnamaldehyde. United States Patent US2529186A. 1950-11-07.
9. Foudah AI, Shakeel F, Alqarni MH, Ross SA, Salkini MA, Alam P. Simultaneous Estimation of Cinnamaldehyde and Eugenol in Essential Oils and Traditional and Ultrasound-Assisted Extracts of Different Species of Cinnamon Using a Sustainable/Green HPTLC Technique. Molecules. 2021;26(7):2054. DOI: 10.3390/molecules26072054; PMID: 33916710; PMCID: PMC8038348.
10. Puspita OE, Ihsan BRP, Saraswati A. Analytical method validation of cinnamaldehyde content in cinnamon (Cinnamomum burmannii) extract using high-performance liquid chromatography. J Med Pharm Allied Sci. 2023;12(4):5976–82. DOI: 10.55522/jmpas.V12I4.5005.
11. Amalia D, Ngadwiyana, Fachriyah E. Sintesis Etil Sinamat dari Sinamaldehid pada Minyak Kayu Manis (Cinnamomum cassia) dan Uji Aktivitas sebagai Antidiabetes. J Sains Mat. 2013;21(4):108-13.
12. Fadl F, Abdalla S, Ishaq A, Umar Y. DFT Study of the Molecular Structure, Conformational Preference, Spectroscopic and Vibrational Analysis of Cinnamic Acid and Cinnamaldehyde. J Mex Chem Soc. 2022;66(4):543–59. DOI: 10.29356/jmcs.v66i4.1757.
13. Purwaningsih Y, Syukur M, Purwanto URE. Sonochemical Synthesis of Ethyl Cinnamate. JKPK J Kimia Pendidikan Kimia). 2020;5(1):1-7. DOI: 10.20961/jkpk.v5i1.35525.
14. Singh N, Yadav SS, Kumar S, Narasihman B, Ramasamy K, Lim SM, et al. Synthesis, characterization, in-vitro and in-silico therapeutic studies of cinnamaldehyde derivatives. J Mol Struct. 2025;1321:140165. DOI: 10.1016/j.molstruc.2024.140165.
15. Dalcanale E, Montanari F. Selective Oxidation of Aldehydes to Carboxylic Acids with Sodium Chlorite-Hydrogen Peroxide. Chem Informationsdienst. 1986;17(34):198634147. DOI: 10.1002/chin.198634147.
16. Hussein AA, Al-Hadedi AAM, Mahrath AJ, Moustafa GAI, Almalki FA, Alqahtani A, Shityakov S, Algazally ME. Mechanistic investigations on Pinnick oxidation: a density functional theory study. R Soc Open Sci. 2020;7(2):191568. DOI: 10.1098/rsos.191568; PMID: 32257322; PMCID: PMC7062072.
17. Yu C, Li YL, Liang M, Dai SY, Ma L, Li WG, et al. Characteristics and hazards of the cinnamaldehyde oxidation process. RSC Adv. 2020;10(32):19124-33. DOI: 10.1039/c9ra10820c; PMID: 35518288; PMCID: PMC9053951.
18. Durndell LJ, Cucuzzella C, Parlett CMA, Isaacs MA, Wilson K, Lee AF. Platinum catalysed aerobic selective oxidation of cinnamaldehyde to cinnamic acid. Catal Today. 2019;333:161–8. DOI: 10.1016/j.cattod.2018.02.052.
19. Aztatzi-Mendoza MA, Porras-Núñez EL, Rivas-Galindo VM, Carranza-Rosales P, Carranza-Torres IE, García-Vielma C, et al. Green synthesis of ethyl cinnamates under microwave irradiation: photophysical properties, cytotoxicity, and cell bioimaging. RSC Adv. 2024;14(4):2391-401. DOI: 10.1039/d3ra06443c; PMID: 38213976; PMCID: PMC10783162.
20. Araújo MO, Pérez-Castillo Y, Oliveira LHG, Nunes FC, Sousa DP. Larvicidal Activity of Cinnamic Acid Derivatives: Investigating Alternative Products for Aedes aegypti L. Control. Molecules. 2020;26(1):61. DOI: 10.3390/molecules26010061; PMID: 33374484; PMCID: PMC7796249.
21. Kciuk M, Gielecińska A, Mujwar S, Kołat D, Kałuzińska-Kołat Ż, Celik I, et al. Doxorubicin-An Agent with Multiple Mechanisms of Anticancer Activity. Cells. 2023;12(4):659. DOI: 10.3390/cells12040659; PMID: 36831326; PMCID: PMC9954613.
22. Ka H, Park HJ, Jung HJ, Choi JW, Cho KS, Ha J, et al. Cinnamaldehyde induces apoptosis by ROS-mediated mitochondrial permeability transition in human promyelocytic leukemia HL-60 cells. Cancer Lett. 2003;196(2):143-52. DOI: 10.1016/s0304-3835(03)00238-6; PMID: 12860272.
23. Ranjitkar S, Zhang D, Sun F, Salman S, He W, Venkitanarayanan K, et al. Cytotoxic effects on cancerous and non-cancerous cells of trans-cinnamaldehyde, carvacrol, and eugenol. Sci Rep. 2021;11(1):16281. DOI: 10.1038/s41598-021-95394-9; PMID: 34381064; PMCID: PMC8358038.
24. Peng J, Song X, Yu W, Pan Y, Zhang Y, Jian H, et al. The role and mechanism of cinnamaldehyde in cancer. J Food Drug Anal. 2024;32(2):140-54. DOI: 10.38212/2224-6614.3502; PMID: 38934689; PMCID: PMC11210466.
25. Wang S, He M, Li L, Liang Z, Zou Z, Tao A. Cell-in-Cell Death Is Not Restricted by Caspase-3 Deficiency in MCF-7 Cells. J Breast Cancer. 2016;19(3):231-41. DOI: 10.4048/jbc.2016.19.3.231; PMID: 27721872; PMCID: PMC5053307.
26. Theodossiou TA, Olsen CE, Jonsson M, Kubin A, Hothersall JS, Berg K. The diverse roles of glutathione-associated cell resistance against hypericin photodynamic therapy. Redox Biol. 2017;12:191-7. DOI: 10.1016/j.redox.2017.02.018; PMID: 28254657; PMCID: PMC5333531.
Authors
1.
Rahmawati NF, Muhtadi M, Suhendi A, Fauzi A, Mujahidin D, Ahwan A, Wibowo A. Rapid and Controlled: Microflow Reactor-Assisted Synthesis of Cinnamaldehyde and Ethyl Cinnamate along with Their Cytotoxic Activity Against Several Cell Lines. Borneo J Pharm [Internet]. 2026Jun.30 [cited 2026Sep.4];9(2):188-97. Available from: https://journal.umpr.ac.id/index.php/bjop/article/view/11781
Copyright (c) 2026 Nindita Fransiska Rahmawati, Muhtadi Muhtadi, Andi Suhendi, Ahmad Fauzi, Didin Mujahidin, Ahwan Ahwan, Agustono Wibowo
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