{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:46:48Z","timestamp":1792025208468,"version":"4.4.0"},"reference-count":119,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The shortage of effective chemotherapeutic agents poses a significant challenge to the global public health system. Cancer is among the leading diseases affecting the human population worldwide. Issues such as drug resistance, toxicity, lack of specificity, poor bioavailability and water solubility, and severe side effects reduce the effectiveness of many existing anticancer drugs. As a result, there is growing interest in discovering a new generation of therapeutic agents to overcome these limitations. Phenolic acids, including ferulic and caffeic acids, are cinnamic acid derivatives with numerous biological effects, including anti-inflammatory, antibacterial, antifungal, antioxidant, antiviral, cytotoxic, and antiproliferative effects. In recent years, drug repurposing and hybridization strategies have emerged as attractive approaches in medicinal chemistry because they may reduce both the cost and time associated with conventional drug discovery. As a result, several researchers have combined ferulic acid and caffeic acid scaffolds with different pharmacophores to generate hybrid compounds with enhanced anticancer potential. This review summarizes recent in vitro and in silico studies published between 2022 and 2025 on ferulic and caffeic acid hybrid compounds that exhibit cytotoxic and antiproliferative effects. Furthermore, the review discusses structure\u2013activity relationship trends, synthetic approaches, and structural modifications associated with improved biological activity. Collectively, the findings highlight the significant potential of ferulic acid and caffeic acid scaffolds in the development of multifunctional anticancer agents.<\/jats:p>","DOI":"10.3390\/molecules31111875","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T15:57:18Z","timestamp":1780070238000},"page":"1875","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Recent Developments in Ferulic Acid- and Caffeic Acid-Based Hybrids with Potential Anticancer Properties"],"prefix":"10.3390","volume":"31","author":[{"given":"Sijongesonke","family":"Peter","sequence":"first","affiliation":[{"name":"Department of Chemical and Earth Sciences, Chemistry Discipline, Faculty of Science and Agriculture, University of Fort Hare, Alice 5700, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda Lunga","family":"Sibali","sequence":"additional","affiliation":[{"name":"Office of the Dean, Faculty of Science and Agriculture, University of Fort Hare, Alice 5700, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vuyolwethu","family":"Khwaza","sequence":"additional","affiliation":[{"name":"Department of Chemical and Earth Sciences, Chemistry Discipline, Faculty of Science and Agriculture, University of Fort Hare, Alice 5700, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athandwe M.","family":"Paca","sequence":"additional","affiliation":[{"name":"Department of Chemical and Earth Sciences, Chemistry Discipline, Faculty of Science and Agriculture, University of Fort Hare, Alice 5700, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,29]]},"reference":[{"key":"ref_1","first-page":"451","article-title":"Global Cancer Statistics 2022: The trends projection analysis","volume":"10","author":"Chhikara","year":"2023","journal-title":"Chem. Biol. Lett."},{"key":"ref_2","first-page":"17","article-title":"Cancer statistics, 2023","volume":"73","author":"Siegel","year":"2023","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1007\/s40121-024-00942-1","article-title":"Epidemiology of Reportable Bacterial Infectious Diseases in Saudi Arabia","volume":"13","author":"Alhumaid","year":"2024","journal-title":"Infect. Dis. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Garcia Martin, A., Fernandez Rodriguez, E.J., Sanchez Gomez, C., and Rihuete Galve, M.I. (2022). Study on the Socio-Economic Impact of Cancer Disease on Cancer Patients and Their Relatives. Healthcare, 10.","DOI":"10.3390\/healthcare10122370"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Ram, B., and Thakur, R. (2022). Epidemiology and Economic Burden of Continuing Challenge of Infectious Diseases in India: Analysis of Socio-Demographic Differentials. Front. Public Health, 10.","DOI":"10.3389\/fpubh.2022.901276"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Haier, J., and Schaefers, J. (2022). Economic Perspective of Cancer Care and Its Consequences for Vulnerable Groups. Cancers, 14.","DOI":"10.3390\/cancers14133158"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2206602","DOI":"10.1002\/advs.202206602","article-title":"Advances of Antimicrobial Peptide-Based Biomaterials for the Treatment of Bacterial Infections","volume":"10","author":"Li","year":"2023","journal-title":"Adv. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"100954","DOI":"10.1016\/j.drup.2023.100954","article-title":"Antimicrobial peptides for combating drug-resistant bacterial infections","volume":"68","author":"Xuan","year":"2023","journal-title":"Drug Resist. Updat."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/s41568-024-00690-x","article-title":"Cancer therapy with antibodies","volume":"24","author":"Paul","year":"2024","journal-title":"Nat. Rev. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ramos, A., Sadeghi, S., and Tabatabaeian, H. (2021). Battling Chemoresistance in Cancer: Root Causes and Strategies to Uproot Them. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22179451"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3029","DOI":"10.1002\/cncr.33587","article-title":"The Ever-Increasing Importance of Cancer as a Leading Cause of Premature Death Worldwide","volume":"127","author":"Bray","year":"2021","journal-title":"Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Liu, Y., Zhu, J., Liu, Z., Zhi, Y., Mei, C., and Wang, H. (2025). Flavonoids as Promising Natural Compounds for Combating Bacterial Infections. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26062455"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1007\/s11030-022-10590-7","article-title":"Recent advances in the area of plant-based anti-cancer drug discovery using computational approaches","volume":"28","author":"Das","year":"2024","journal-title":"Mol. Divers."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"155600","DOI":"10.1016\/j.phymed.2024.155600","article-title":"Phytomedicine Natural products and derivatives for breast cancer treatment: From drug discovery to molecular mechanism","volume":"129","author":"Zhang","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"184","DOI":"10.3390\/ddc3010011","article-title":"Plant-Derived Natural Products: A Source for Drug Discovery and Development","volume":"3","author":"Chaachouay","year":"2024","journal-title":"Drugs Drug Candidates"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s13659-020-00293-7","article-title":"Natural Products in Cancer Therapy:Past, Present and Future","volume":"11","author":"Huang","year":"2021","journal-title":"Nat. Prod. Bioprospect."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Asma, S.T., Acaroz, U., Imre, K., Morar, A., Shah, S.R.A., Hussain, S.Z., Arslan-Acaroz, D., Demirbas, H., Hajrulai-Musliu, Z., and Istanbullugil, F.R. (2022). Natural Products\/Bioactive Compounds as a Source of Anticancer Drugs. Cancers, 14.","DOI":"10.3390\/cancers14246203"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2256871","DOI":"10.1155\/ijfo\/2256871","article-title":"Potential Therapeutic Efficacy of Ferulic Acid and Its Derivatives in the Management of Cancers: A Comprehensive Analysis With Mechanistic Insight","volume":"2025","author":"Ahmmed","year":"2025","journal-title":"Int. J. Food Sci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Cortez, N., Villegas, C., Burgos, V., Cabrera-Pardo, J.R., Ortiz, L., Gonz\u00e1lez-Chavarr\u00eda, I., Nchiozem-Ngnitedem, V.-A., and Paz, C. (2024). Adjuvant Properties of Caffeic Acid in Cancer Treatment. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25147631"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4168","DOI":"10.1002\/jsfa.13931","article-title":"Ferulic acid: Extraction, estimation, bioactivity and applications for human health and food","volume":"105","author":"Kumar","year":"2025","journal-title":"J. Sci. Food Agric."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Pavlikova, N. (2023). Caffeic Acid and Diseases\u2014Mechanisms of Action. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010588"},{"key":"ref_22","first-page":"e68063","article-title":"Ferulic Acid: A Comprehensive Review","volume":"16","author":"Purushothaman","year":"2024","journal-title":"Cureus"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"119921","DOI":"10.1016\/j.lfs.2021.119921","article-title":"Ferulic acid: A review of its pharmacology, pharmacokinetics and derivatives","volume":"284","author":"Li","year":"2021","journal-title":"Life Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1007\/s43440-023-00494-0","article-title":"Molecular mechanism of ferulic acid and its derivatives in tumor progression","volume":"75","author":"Bao","year":"2023","journal-title":"Pharmacol. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Alam, M., Ahmed, S., Elasbali, A.M., Adnan, M., Alam, S., Hassan, M.I., and Pasupuleti, V.R. (2022). Therapeutic Implications of Caffeic Acid in Cancer and Neurological Diseases. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.860508"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1186\/s12935-018-0595-y","article-title":"The anticancer effects of ferulic acid is associated with induction of cell cycle arrest and autophagy in cervical cancer cells","volume":"18","author":"Gao","year":"2018","journal-title":"Cancer Cell Int."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Chen, S., Zhao, D., Luan, C., Zheng, J., Liu, W., Feng, Z., Luo, R., Han, X., and Wang, D. (2023). Ferulic Acid Induces Autophagy and Apoptosis in Colon Cancer CT26 Cells via the MAPK Pathway. Molecules, 28.","DOI":"10.3390\/molecules28166014"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Chen, C., Kuo, Y.H., Lin, C.C., Chao, C.Y., Pai, M.H., Chiang, E.P.I., and Tang, F.Y. (2020). Decyl caffeic acid inhibits the proliferation of colorectal cancer cells in an autophagy-dependent manner in vitro and in vivo. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0232832"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Shih, Y.H., Chen, C.C., Kuo, Y.H., Fuh, L.J., Lan, W.C., Wang, T.H., Chiu, K.C., Nguyen, T.H.V., Hsia, S.M., and Shieh, T.M. (2023). Caffeic Acid Phenethyl Ester and Caffeamide Derivatives Suppress Oral Squamous Cell Carcinoma Cells. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24129819"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.ejphar.2015.09.044","article-title":"The effects of caffeic, coumaric and ferulic acids on proliferation, superoxide production, adhesion and migration of human tumor cells in vitro","volume":"766","author":"Bouzaiene","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9437","DOI":"10.1007\/s13277-015-3689-3","article-title":"Assessment of the anticancer mechanism of ferulic acid via cell cycle and apoptotic pathways in human prostate cancer cell lines","volume":"36","author":"Dodurga","year":"2015","journal-title":"Tumor Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.mehy.2013.02.003","article-title":"Caffeic acid phenethyl ester as an adjuvant therapy for advanced prostate cancer","volume":"80","author":"Liu","year":"2013","journal-title":"Med. Hypotheses"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e920095","DOI":"10.12659\/MSM.920095","article-title":"Ferulic Acid Induces Apoptosis of HeLa and Caski Cervical Carcinoma Cells by Down-Regulating the Phosphatidylinositol 3-Kinase (PI3K)\/Akt Signaling Pathway","volume":"26","author":"Luo","year":"2020","journal-title":"Med. Sci. Monit."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Tyszka-Czochara, M., Konieczny, P., and Majka, M. (2017). Caffeic Acid Expands Anti-Tumor Effect of Metformin in Human Metastatic Cervical Carcinoma HTB-34 Cells: Implications of AMPK Activation and Impairment of Fatty Acids De Novo Biosynthesis. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18020462"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.redox.2016.12.006","article-title":"The timing of ca ff eic acid treatment with cisplatin determines sensitization or resistance of ovarian carcinoma cell lines","volume":"11","author":"Sirota","year":"2017","journal-title":"Redox Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1016\/j.biopha.2018.01.129","article-title":"Caffeic acid phenethyl ester inhibits the progression of ovarian cancer by regulating NF-\u03baB signaling","volume":"99","author":"Liu","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Sung, H.C., Chang, K.S., Chen, S.T., Hsu, S.Y., Lin, Y.H., Hou, C.P., Feng, T.H., Tsui, K.H., and Juang, H.H. (2022). Metallothionein 2A with Antioxidant and Antitumor Activity Is Upregulated by Caffeic Acid Phenethyl Ester in Human Bladder Carcinoma Cells. Antioxidants, 11.","DOI":"10.3390\/antiox11081509"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.cpan.2025.11.002","article-title":"Ferulic acid targets AKT1\/STAT3\/EGFR signaling to induce apoptosis and inhibit metastasis in gastric cancer cells","volume":"22","author":"Liu","year":"2026","journal-title":"Curr. Pharm. Anal."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"38","DOI":"10.3109\/10520295.2015.1072769","article-title":"Effects of caffeic acid phenethyl ester on matrix molecules and angiogenetic and anti-angiogenetic factors in gastric cancer cells cultured on different substrates","volume":"91","author":"Kosova","year":"2016","journal-title":"Biotech. Histochem."},{"key":"ref_40","first-page":"225","article-title":"In vitro cytotoxicity assessment of ferulic, caffeic and p-coumaric acids on human renal cancer cells","volume":"17","author":"Caparica","year":"2020","journal-title":"Biomed. Biopharm. Res."},{"key":"ref_41","first-page":"e81969","article-title":"Cytotoxic and Apoptotic Effects of Ferulic Acid on Renal Carcinoma","volume":"15","author":"Karimvand","year":"2020","journal-title":"Jundishapur J. Nat. Pharm. Prod."},{"key":"ref_42","first-page":"2571","article-title":"Antiproliferative and proapoptotic activities of ferulic acid in breast and liver cancer cell lines","volume":"18","author":"ElKhazendar","year":"2019","journal-title":"Trop. J. Pharm. Res."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Esp\u00edndola, K.M.M., Ferreira, R.G., Narvaez, L.E.M., Silva Rosario, A.C.R., Da Silva, A.H.M., Silva, A.G.B., Vieira, A.P.O., and Monteiro, M.C. (2019). Chemical and Pharmacological Aspects of Caffeic Acid and Its Activity in Hepatocarcinoma. Front. Oncol., 9.","DOI":"10.3389\/fonc.2019.00541"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6684","DOI":"10.18632\/oncotarget.3246","article-title":"Caffeic acid phenethyl ester induced cell cycle arrest and growth inhibition in androgen-independent prostate cancer cells via regulation of Skp2, p53, p21Cip1 and p27Kip1","volume":"6","author":"Lin","year":"2015","journal-title":"Oncotarget"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Singh Tuli, H., Kumar, A., Ramniwas, S., Coudhary, R., Aggarwal, D., Kumar, M., Sharma, U., Chaturvedi Parashar, N., Haque, S., and Sak, K. (2022). Ferulic Acid: A Natural Phenol That Inhibits Neoplastic Events through Modulation of Oncogenic Signaling. Molecules, 27.","DOI":"10.3390\/molecules27217653"},{"key":"ref_46","first-page":"1850732","article-title":"Antiproliferative Effects of Ferulic, Coumaric, and Caffeic Acids in HepG2 Cells by hTERT Downregulation","volume":"2022","author":"Afshari","year":"2022","journal-title":"Adv. Pharmacol. Pharm. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Markowska, A., Markowska, J., Stanis\u0142awiak-Rudowicz, J., Kozak, K., Roubinek, O.K., and Jasi\u0144ska, M. (2025). The Role of Ferulic Acid in Selected Malignant Neoplasms. Molecules, 30.","DOI":"10.3390\/molecules30051018"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Chiang, E.P.I., Tsai, S.Y., Kuo, Y.H., Pai, M.H., Chiu, H.L., Rodriguez, R.L., and Tang, F.Y. (2014). Caffeic Acid Derivatives Inhibit the Growth of Colon Cancer: Involvement of the PI3-K\/Akt and AMPK Signaling Pathways. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0099631"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"116556","DOI":"10.1016\/j.biopha.2024.116556","article-title":"Caffeic acid alleviates skeletal muscle atrophy in 5\/6 nephrectomy rats through the TLR4\/MYD88\/NF-kB pathway","volume":"174","author":"He","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"101","DOI":"10.12923\/cipms-2025-0016","article-title":"A study on design, virtual screening, and docking analysis of new ferulic acid analogs against the NF-\u03baB therapeutic target","volume":"38","author":"Mayana","year":"2025","journal-title":"Curr. Issues Pharm. Med. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Alam, M., Ashraf, G.M., Sheikh, K., Khan, A., Ali, S., Ansari, M.M., Adnan, M., Pasupuleti, V.R., and Hassan, M.I. (2022). Potential Therapeutic Implications of Caffeic Acid in Cancer Signaling: Past, Present, and Future. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.845871"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Ezzat, S.M., Teba, H.E.S., Shahin, I.G., Hafez, A.M., Kamal, A.M., and Aborehab, N.M. (2022). Development of Semisynthetic Apoptosis-Inducing Agents Based on Natural Phenolic Acids Scaffold: Design, Synthesis and In-Vitro Biological Evaluation. Molecules, 27.","DOI":"10.3390\/molecules27196724"},{"key":"ref_53","first-page":"1781","article-title":"Effect of Caffeic Acid on Nitrophenylethyl Ester through Regulating EGFR\/STAT3\/Akt Pathway Related Proteins on Triple Negative Breast Cancer","volume":"85","author":"Huang","year":"2023","journal-title":"Indian J. Pharm. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s11094-025-03363-7","article-title":"Effects of caffeic acid on human health: Pharmacological and therapeutic effects, biological activity and toxicity","volume":"59","author":"Yazar","year":"2025","journal-title":"Pharm. Chem. J."},{"key":"ref_55","first-page":"19470","article-title":"Design and synthesis of hybrid compounds as novel drugs and medicines","volume":"12","author":"Alkhzem","year":"2022","journal-title":"R. Soc. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Singh, A.K., Kumar, A., Singh, H., Sonawane, P., Paliwal, H., Thareja, S., Pathak, P., Grishina, M., Jaremko, M., and Emwas, A.-H. (2022). Concept of Hybrid Drugs and Recent Advancements in Anticancer Hybrids. Pharmaceuticals, 15.","DOI":"10.3390\/ph15091071"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"108604","DOI":"10.1016\/j.cmpb.2025.108604","article-title":"Drug repurposing using artificial intelligence, molecular docking, and hybrid approaches: A comprehensive review in general diseases vs Alzheimer\u2019s disease","volume":"261","author":"Zulhafiz","year":"2025","journal-title":"Comput. Methods Programs Biomed."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Wilkins, C.A., Hamman, H., Hamman, J.H., and Steenekamp, J.H. (2024). Fixed-Dose Combination Formulations in Solid Oral Drug Therapy: Advantages, Limitations, and Design Features. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16020178"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Marques, L., Costa, B., Pereira, M., Silva, A., Santos, J., Saldanha, L., Silva, I., Magalh\u00e3es, P., Schmidt, S., and Vale, N. (2024). Advancing Precision Medicine: A Review of Innovative In Silico Approaches for Drug Development, Clinical Pharmacology and Personalized Healthcare. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16030332"},{"key":"ref_60","first-page":"578","article-title":"The importance of in-silico studies in drug discovery","volume":"2","author":"Roney","year":"2024","journal-title":"Intell. Pharm."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1007\/s00044-024-03260-w","article-title":"In silico drug discovery: A machine learning-driven systematic review","volume":"33","author":"Atasever","year":"2024","journal-title":"Med. Chem. Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41392-024-01808-1","article-title":"Drug repurposing for cancer therapy","volume":"9","author":"Xia","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.semcancer.2020.02.003","article-title":"Turning liabilities into opportunities: Off-target based drug repurposing in cancer","volume":"68","author":"Palve","year":"2021","journal-title":"Semin. Cancer Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1007\/s00210-022-02263-x","article-title":"Drug repurposing\u2014An emerging strategy in cancer therapeutics","volume":"395","author":"Turabi","year":"2022","journal-title":"Naunyn-Schmiedebergs Arch. Pharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"4910","DOI":"10.7150\/thno.56205","article-title":"Theranostics Drug repurposing for next-generation combination therapies against multidrug-resistant bacteria","volume":"11","author":"Liu","year":"2021","journal-title":"Theranostics"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.1016\/j.drudis.2022.05.006","article-title":"Drug repurposing to overcome microbial resistance","volume":"27","author":"Jampilek","year":"2022","journal-title":"Drug Discov. Today"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"895","DOI":"10.2174\/1874467215666220214104530","article-title":"Drug Repurposing for Cancer Therapy in the Era of Precision Medicine","volume":"15","author":"To","year":"2022","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Glajzner, P., Bernat, A., and Jasi\u0144ska-Stroschein, M. (2024). Improving the treatment of bacterial infections caused by multidrug-resistant bacteria through drug repositioning. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1397602"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Tsopka, I.C., and Hadjipavlou-Litina, D. (2021). Hybrids as NO Donors. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22189788"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"5753","DOI":"10.1007\/s11696-024-03498-z","article-title":"Coumarin hybrids: A sighting of their roles in drug targeting","volume":"78","author":"Zeki","year":"2024","journal-title":"Chem. Pap."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"102383","DOI":"10.1016\/j.pmpp.2024.102383","article-title":"Exploring phenolic compounds as natural stress alleviators in plants-a comprehensive review","volume":"133","author":"Saini","year":"2024","journal-title":"Physiol. Mol. Plant Pathol."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Abotaleb, M., Liskova, A., Kubatka, P., and B\u00fcsselberg, D. (2020). Therapeutic Potential of Plant Phenolic Acids in the Treatment of Cancer. Biomolecules, 10.","DOI":"10.3390\/biom10020221"},{"key":"ref_73","first-page":"1","article-title":"A Brief Review of Phenolic Compounds Identified from Plants: Their Extraction, Analysis, and Biological Activity","volume":"17","author":"Zhang","year":"2022","journal-title":"Nat. Prod. Commun."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1007\/s11101-020-09689-2","article-title":"Biosynthesis and metabolic actions of simple phenolic acids in plants","volume":"19","author":"Marchiosi","year":"2020","journal-title":"Phytochem. Rev."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1039\/D0FO02324H","article-title":"Phenolic compounds: Current industrial applications, limitations and future challenges","volume":"12","author":"Albuquerque","year":"2021","journal-title":"Food Funct."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2765","DOI":"10.1080\/10408398.2024.2350616","article-title":"Encapsulation of phenolic acids within food-grade carriers systems: A systematic review","volume":"65","author":"Chen","year":"2025","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"293","DOI":"10.22271\/journalofsport.2021.v6.i1e.2236","article-title":"Classifications of polyphenols and their potential application in human health and diseases","volume":"6","author":"Prabhu","year":"2021","journal-title":"Int. J. Physiol. Nutr. Phys. Educ."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1007\/s00210-024-03396-x","article-title":"Anticancer potential of hydroxycinnamic acids: Mechanisms, bioavailability, and therapeutic applications","volume":"398","author":"Ceylan","year":"2025","journal-title":"Naunyn-Schmiedebergs Arch. Pharmacol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/bs.apcsb.2020.12.005","article-title":"Chapter Eight\u2014Ferulic acid-mediated modulation of apoptotic signaling pathways in cancer","volume":"125","author":"Gupta","year":"2021","journal-title":"Adv. Protein Chem. Struct. Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/s13205-025-04469-1","article-title":"Synergistic targeting of cancer-related proteins by benzyl isothiocyanate and caffeic acid: MLSD and cytotoxic mechanisms in MCF-7 cells","volume":"15","author":"Rahaman","year":"2025","journal-title":"3 Biotech."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"140080","DOI":"10.1016\/j.foodchem.2024.140080","article-title":"Plant-derived and dietary phenolic cinnamic acid derivatives: Anti-inflammatory properties","volume":"459","author":"Freitas","year":"2024","journal-title":"Food Chem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"129255","DOI":"10.1016\/j.molstruc.2020.129255","article-title":"Design, synthesis, anticancer and antioxidant activities of amide linked 1,4-disubstitute d 1,2,3-triazoles","volume":"1226","author":"Kaushik","year":"2021","journal-title":"J. Mol. Struct."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"18082","DOI":"10.1021\/acs.jmedchem.1c01496","article-title":"Amide-to-Ester Substitution as a Strategy for Optimizing PROTAC Permeability and Cellular Activity","volume":"64","author":"Klein","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Mingoia, M., Conte, C., Di Rienzo, A., Dimmito, M.P., Marinucci, L., Magi, G., Turkez, H., Cufaro, M.C., Del Boccio, P., and Di Stefano, A. (2022). Synthesis and Biological Evaluation of Novel Cinnamic Acid-Based Antimicrobials. Pharmaceuticals, 15.","DOI":"10.3390\/ph15020228"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Peter, S., Morifi, E., Nwamadi, M., Oselusi, S.O., Tantoh, A.L., Fonkui, T.Y., Ndinteh, D.T., and Aderibigbe, B.A. (2025). Ferrocene-Based Hybrid Drugs as Potential Anticancer and Antibacterial Therapeutic Agents for Incorporation into Nanocarriers: In Silico, In Vitro, Molecular Docking Evaluations. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17060722"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1016\/S1470-2045(20)30424-1","article-title":"Drug repurposing for cancer treatments: A well-intentioned, but misguided strategy","volume":"21","author":"Tran","year":"2020","journal-title":"Lancet Oncol."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Peter, S., Sotondoshe, N., and Aderibigbe, B.A. (2024). Carvacrol and Thymol Hybrids: Potential Anticancer and Antibacterial Therapeutics. Molecules, 29.","DOI":"10.3390\/molecules29102277"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Chunarkar-Patil, P., Kaleem, M., Mishra, R., Ray, S., Ahmad, A., Verma, D., Bhayye, S., Dubey, R., Singh, H.N., and Kumar, S. (2024). Anticancer Drug Discovery Based on Natural Products: From Computational Approaches to Clinical Studies. Biomedicines, 12.","DOI":"10.3390\/biomedicines12010201"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"e202500447","DOI":"10.1002\/cmdc.202500447","article-title":"Recent Insights in Multi-Target Drugs in Pharmacology and Medicinal Chemistry","volume":"20","author":"Cemali","year":"2025","journal-title":"ChemMedChem"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1002\/med.22113","article-title":"Harnessing the Power of Natural Products for Targeted Protein Degradation","volume":"45","author":"Zhu","year":"2025","journal-title":"Med. Res. Rev."},{"key":"ref_91","unstructured":"Soltau, C.P. (2026). Exploring the Potential of Nitroxide-Steroidal Hybridised Compounds as Redox Modulating Anti-Inflammatory Drugs. [Doctoral Dissertation, Queensland University of Technology]."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1021\/acsmedchemlett.4c00099","article-title":"Synthesis and in Vitro Evaluation of CAPE Derivatives as Ferroptosis Inducers in Triple Negative Breast Cancer","volume":"15","author":"Consoli","year":"2024","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"154860","DOI":"10.1016\/j.phymed.2023.154860","article-title":"Caffeic acid phenethyl ester suppresses EGFR\/FAK\/Akt signaling, migration, and tumor growth of prostate cancer cells","volume":"116","author":"Tseng","year":"2023","journal-title":"Phytomedicine"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"6086","DOI":"10.4067\/s0717-97072024000206086","article-title":"Synthesis of Curcumin-ferulic acid conjugate via Steglich esterification and anti-lung cancer activity of against Human non-small lung cancer cells (NSLCC)","volume":"69","author":"Cheng","year":"2024","journal-title":"J. Chil. Chem. Soc."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1007\/s11030-025-11264-w","article-title":"Design, synthesis, and in vitro and in vivo anticancer activity of mitochondrial targeted ferulic acid derivatives","volume":"30","author":"Wu","year":"2026","journal-title":"Mol. Divers."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Luk\u00e1\u010d, M., Slobodn\u00edkov\u00e1, L., Mrva, M., Du\u0161ekov\u00e1, A., Garajov\u00e1, M., Kello, M., \u0160ebov\u00e1, D., Pis\u00e1r\u010dik, M., Kojnok, M., and Vrt\u00e1k, A. (2024). Caffeic Acid Phosphanium Derivatives: Potential Selective Antitumor, Antimicrobial and Antiprotozoal Agents. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25021200"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"141700","DOI":"10.1016\/j.molstruc.2025.141700","article-title":"Design, synthesis and biological evaluation of chromene-oxadiazole amide hybrids with phenolic acids","volume":"1332","author":"Jadhaw","year":"2025","journal-title":"J. Mol. Struct."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Nikolova-Mladenova, B., Momekov, G., Zhivkova, Z., and Doytchinova, I. (2023). Design, Synthesis and Cytotoxic Activity of Novel Salicylaldehyde Hydrazones against Leukemia and Breast Cancer. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24087352"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"13129","DOI":"10.1039\/D4RA01683A","article-title":"The conjugates of 50-deoxy-5-fluorocytidine and hydroxycinnamic acids\u2014Synthesis, anti-pancreatic cancer activity and molecular docking studies","volume":"14","author":"Cybulski","year":"2024","journal-title":"RSC Adv."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"116809","DOI":"10.1016\/j.bmc.2022.116809","article-title":"Bioorganic & Medicinal Chemistry Discovery of novel chloropyramine-cinnamic acid hybrids as potential FAK inhibitors for intervention of metastatic triple-negative breast cancer","volume":"66","author":"Yang","year":"2022","journal-title":"Bioorg. Med. Chem."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Fonseca, R., Louzano, Y.D.S., Ortiz, C.J.C., Silva, M.D.F., Felix, M.L.V., Ferreira-Silva, G.\u00c1., Caixeta, E.S., Zavan, B., Viegas, C., and Ionta, M. (2025). Curcumin-like Compound Inhibits Proliferation of Adenocarcinoma Cells by Inducing Cell Cycle Arrest and Senescence. Pharmaceuticals, 18.","DOI":"10.3390\/ph18060914"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.tiv.2018.02.020","article-title":"Synthetic resveratrol-curcumin hybrid derivative inhibits mitosis progression in estrogen positive MCF-7 breast cancer cells","volume":"50","author":"Coelho","year":"2018","journal-title":"Toxicol. Vitr."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"e202403199","DOI":"10.1002\/cbdv.202403199","article-title":"Synthesis and Anticancer Activity of Metformin-Phenolic Acid Conjugates","volume":"22","author":"Banerjee","year":"2025","journal-title":"Chem. Biodivers."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1007\/s00044-025-03396-3","article-title":"Discovery of structurally novel tetrahydroisoquinoline derivatives bearing NO donor as potential anti-cancer therapeutics","volume":"34","author":"Chen","year":"2025","journal-title":"Med. Chem. Res."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Cybulski, M., Sidoryk, K., Zaremba-Czogalla, M., Trzaskowski, B., Kubiszewski, M., Tobiasz, J., Jaromin, A., and Michalak, O. (2024). The Conjugates of Indolo [2,3-b] quinoline as Anti-Pancreatic Cancer Agents: Design, Synthesis, Molecular Docking and Biological Evaluations. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25052573"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Nath, R., Ashique, S., Nehra, B., Debnath, I., Ghosh, S., Chawla, P.A., Al-Salem, F.M., Yasmin, S., Hussain, M.S., and Das, L. (2026). Rational drug design and synthesis of novel bioactive molecules with oxygen heterocycles, including AChE and BChE inhibitory properties and SAR studies. Mol. Divers., Epub ahead of printing.","DOI":"10.1007\/s11030-026-11499-1"},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"El-Masry, R.M., Kadry, H.H., Taher, A.T., and Abou-Seri, S.M. (2022). Comparative Study of the Synthetic Approaches and Biological Activities of the Bioisosteres of 1,3,4-Oxadiazoles and 1,3,4-Thiadiazoles over the Past Decade. Molecules, 27.","DOI":"10.3390\/molecules27092709"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1021\/acsptsci.5c00646","article-title":"Bioisosteric Replacement of Amides with 1,2,3-Triazoles Improves Dopamine D4 Receptor Ligand Pharmacokinetics","volume":"9","author":"Alkhatib","year":"2026","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_109","first-page":"3","article-title":"Novel Heterocyclic Scaffolds in Drug Discovery: Design Strategies and Therapeutic Applications","volume":"1","author":"Kumar","year":"2025","journal-title":"BioNexus Bull."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"13094","DOI":"10.1039\/D5CC02443A","article-title":"Iridium-catalysed direct C\u2013H functionalisation as a platform for stereoselective C\u2013C bond formation","volume":"61","author":"Yamakawa","year":"2025","journal-title":"Chem. Commun."},{"key":"ref_111","first-page":"1444","article-title":"Synthesis, Characterization, and Preliminary Evaluation of Ferulic Acid Derivatives Containing Heterocyclic Moiety","volume":"6","author":"Malik","year":"2023","journal-title":"J. Med. Chem. Sci."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"134833","DOI":"10.1016\/j.tet.2025.134833","article-title":"Progress in the synthesis and applications of FDA-approved anticancer drugs: Current trends and future perspectives","volume":"185","author":"Khan","year":"2025","journal-title":"Tetrahedron"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"e70099","DOI":"10.1002\/ddr.70099","article-title":"Novel Oxadiazole-Based Bioisostere of Caffeic Acid Phenethyl Ester: Synthesis, Anticancer Activity, and Inhibition of Lipoxygenase Product Biosynthesis","volume":"86","author":"Robichaud","year":"2025","journal-title":"Drug Dev. Res."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1080\/14756366.2022.2027933","article-title":"Comparative chemical and biological hydrolytic stability of homologous esters and isosteres","volume":"37","author":"Guedes","year":"2022","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1080\/17460441.2022.2129613","article-title":"The 1,2,3-triazole \u2018all-in-one\u2019 ring system in drug discovery: A good bioisostere, a good pharmacophore, a good linker, and a versatile synthetic tool","volume":"17","author":"Lengerli","year":"2022","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Sehrawat, R., Pasrija, R., Rathee, P., Kumari, D., Khatkar, A., K\u00fcpeli Akkol, E., and Sobarzo-S\u00e1nchez, E. (2024). Hybrid Caffeic Acid-Based DHFR Inhibitors as Novel Antimicrobial and Anticancer Agents. Antibiotics, 13.","DOI":"10.3390\/antibiotics13060479"},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Sehrawat, R., Pasrija, R., Rathee, P., Kumari, D., and Khatkar, A. (2024). Molecular modeling, synthesis and biological evaluation of caffeic acid based Dihydrofolate reductase inhibitors. BMC Chem., 18.","DOI":"10.1186\/s13065-024-01355-4"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"108160","DOI":"10.1016\/j.jmgm.2022.108160","article-title":"Design and synthesis of novel caffeic acid phenethyl ester (CAPE) derivatives and their biological activity studies in glioblastoma multiforme (GBM) cancer cell lines","volume":"113","author":"Sucu","year":"2022","journal-title":"J. Mol. Graph. Model."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.55730\/1300-0527.3417","article-title":"Synthesis of novel oxadiazole derivatives and their cytotoxic activity against various cancer cell lines","volume":"46","author":"Sucu","year":"2022","journal-title":"Turk. J. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/11\/1875\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T04:36:39Z","timestamp":1780634199000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/11\/1875"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,29]]},"references-count":119,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["molecules31111875"],"URL":"https:\/\/doi.org\/10.3390\/molecules31111875","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,29]]}}}