{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T22:20:41Z","timestamp":1778538041090,"version":"3.51.4"},"reference-count":50,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,11]],"date-time":"2023-02-11T00:00:00Z","timestamp":1676073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004837","name":"Spanish Ministry of Science and Innovation","doi-asserted-by":"publisher","award":["DIN2019-010829"],"award-info":[{"award-number":["DIN2019-010829"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Plants have been used by humans since ancient times due their antimicrobial and medicinal properties. Essential oils (EOs) are complex mixtures of secondary plant metabolites, including terpenoids, phenylpropanoids, and other aromatic compounds. Cinnamomun verum and Thyme vulgaris EOs and their organic extracts exert numerous biological activities because of their major compounds, particularly thymol, carvacrol, eugenol, and benzoic and cinnamic acid. The structural motifs presented by these phytochemicals are responsible for their biological activities. Modification or hybridization of these structures could lead to new bio-based compounds with improved efficacy or multiple modes of action. In this work, we aimed to develop reliable methods of obtaining six hybrid molecules from the major constituents of C. verum and T. vulgaris EOs. For the first time, we tested their efficacy in the inhibition of the mycelium growth and spore germination of two of the most important phytopathogenic fungi, Fusarium oxysporum and Colletotrichum gloeosporioides, and one opportunistic human pathogen, Aspergillus niger. The cytotoxic activity of the obtained hybrids was assessed using the brine shrimp lethality assay. In addition, we report for the first time a biocatalytic process for the obtention of these bioactive hybrid molecules. The results of this work enable the possibility of using hybrid molecules based on the major constituents of EOs as active ingredients in strategic industries such as agriculture, aquaculture, and pharmaceuticals.<\/jats:p>","DOI":"10.3390\/life13020499","type":"journal-article","created":{"date-parts":[[2023,2,13]],"date-time":"2023-02-13T04:07:19Z","timestamp":1676261239000},"page":"499","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Biological Activity of Hybrid Molecules Based on Major Constituents of Cinnammomun verum and Thymus vulgaris Essential Oils"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5201-4899","authenticated-orcid":false,"given":"Juan","family":"Valverde Sancho","sequence":"first","affiliation":[{"name":"Green Chemistry Area, R&D Department, Kimitec Group, Paraje Cerro de Los Lobos, 04738 V\u00edcar, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0657-9848","authenticated-orcid":false,"given":"Cristina","family":"Carre\u00f1o Amate","sequence":"additional","affiliation":[{"name":"Phytopathology Area, R&D Department, Kimitec Group, Paraje Cerro de Los Lobos, 04738 V\u00edcar, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda del Mar","family":"Caparr\u00f3s P\u00e9rez","sequence":"additional","affiliation":[{"name":"Green Chemistry Area, R&D Department, Kimitec Group, Paraje Cerro de Los Lobos, 04738 V\u00edcar, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Omar","family":"Santana M\u00e9ridas","sequence":"additional","affiliation":[{"name":"Phytochemistry Area, R&D Department, Kimitec Group, Paraje Cerro de Los Lobos, 04738 V\u00edcar, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8534-4133","authenticated-orcid":false,"given":"Luis F.","family":"Julio","sequence":"additional","affiliation":[{"name":"Green Chemistry Area, R&D Department, Kimitec Group, Paraje Cerro de Los Lobos, 04738 V\u00edcar, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5190603","DOI":"10.1155\/2020\/5190603","article-title":"Chemical Composition and Antioxidant, Antimicrobial, and Antiproliferative Activities of Cinnamomum Zeylanicum Bark Essential Oil","volume":"2020","author":"Falah","year":"2020","journal-title":"Evid.-Based Complement. Altern. Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Galovi\u010dov\u00e1, L., Borotov\u00e1, P., Valkov\u00e1, V., Vukovic, N.L., Vukic, M., \u0160tef\u00e1nikov\u00e1, J., \u010e\u00faranov\u00e1, H., Kowalczewski, P.\u0141., \u010cmikov\u00e1, N., and Ka\u010d\u00e1niov\u00e1, M. (2021). Thymus Vulgaris Essential Oil and Its Biological Activity. Plants, 10.","DOI":"10.3390\/plants10091959"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Kubatka, P., Uramova, S., Kello, M., Kajo, M., Samec, M., Jasek, K., Vybohova, D., Liskova, A., Mojzis, J., and Adamkov, M. (2019). Anticancer Activities of Thymus vulgaris L. in Experimental Breast Carcinoma in Vivo and in Vitro. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20071749"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Nu\u021b\u0103, D.C., Limban, C., Chiri\u021b\u0103, C., Chifiriuc, M.C., Costea, T., Ioni\u021b\u0103, P., Nicolau, I., and Zarafu, I. (2021). Contribution of Essential Oils to the Fight against Microbial Biofilms\u2014A Review. Processes, 9.","DOI":"10.3390\/pr9030537"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Ebadollahi, A., Ziaee, M., and Palla, F. (2020). Essential Oils Extracted from Different Species of the Lamiaceae Plant Family as Prospective Bioagents against Several Detrimental Pests. Molecules, 25.","DOI":"10.3390\/molecules25071556"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Abd El-Hack, M.E., Alagawany, M., Abdel-Moneim, A.-M.E., Mohammed, N.G., Khafaga, A.F., Bin-Jumah, M., Othman, S.I., Allam, A.A., and Elnesr, S.S. (2020). Cinnamon (Cinnamomum zeylanicum) Oil as a Potential Alternative to Antibiotics in Poultry. Antibiotics, 9.","DOI":"10.3390\/antibiotics9050210"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1080\/1040841X.2017.1295225","article-title":"Antimicrobial Activity of Eugenol and Essential Oils Containing Eugenol: A Mechanistic Viewpoint","volume":"43","author":"Marchese","year":"2017","journal-title":"Crit. Rev. Microbiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3957262","DOI":"10.1155\/2018\/3957262","article-title":"An Overview on the Anti-Inflammatory Potential and Antioxidant Profile of Eugenol","volume":"2018","author":"Barboza","year":"2018","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"B\u0142aszczyk, N., Rosiak, A., and Ka\u0142u\u017cna-Czapli\u0144ska, J. (2021). The Potential Role of Cinnamon in Human Health. Forests, 12.","DOI":"10.3390\/f12050648"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1080\/0972060X.2014.971069","article-title":"Chemical Profile, Antioxidant and Antibacterial Activity of Thyme and Oregano Essential Oils, Thymol and Carvacrol and Their Possible Synergism","volume":"18","author":"Gavaric","year":"2015","journal-title":"J. Essent. Oil Bear. Plants"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3042","DOI":"10.1080\/10408398.2019.1675585","article-title":"The Antibacterial Properties of Phenolic Isomers, Carvacrol and Thymol","volume":"60","author":"Kachur","year":"2020","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Kowalczyk, A., Przychodna, M., Sopata, S., Bodalska, A., and Fecka, I. (2020). Thymol and Thyme Essential Oil\u2014New Insights into Selected Therapeutic Applications. Molecules, 25.","DOI":"10.3390\/molecules25184125"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.jare.2020.12.010","article-title":"A Value-Added Application of Eugenol as Acaricidal Agent: The Mechanism of Action and the Safety Evaluation","volume":"34","author":"Shang","year":"2021","journal-title":"J. Adv. Res."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Bezerra, D., Milit\u00e3o, G., de Morais, M., and de Sousa, D. (2017). The Dual Antioxidant\/Prooxidant Effect of Eugenol and Its Action in Cancer Development and Treatment. Nutrients, 9.","DOI":"10.3390\/nu9121367"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"116819","DOI":"10.1016\/j.lfs.2019.116819","article-title":"Cinnamic Acid Rescues Behavioral Deficits in a Mouse Model of Traumatic Brain Injury by Targeting MiR-455-3p\/HDAC2","volume":"235","author":"Guo","year":"2019","journal-title":"Life Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5721585","DOI":"10.1155\/2019\/5721585","article-title":"Benzoic Acid Used as Food and Feed Additives Can Regulate Gut Functions","volume":"2019","author":"Mao","year":"2019","journal-title":"BioMed Res. Int."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"19292","DOI":"10.3390\/molecules191219292","article-title":"Natural Cinnamic Acids, Synthetic Derivatives and Hybrids with Antimicrobial Activity","volume":"19","author":"Guzman","year":"2014","journal-title":"Molecules"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/s10295-015-1710-x","article-title":"Natural Product Derived Insecticides: Discovery and Development of Spinetoram","volume":"43","author":"Galm","year":"2016","journal-title":"J. Ind. Microbiol. Biotechnol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"259","DOI":"10.2174\/1574892810666150708110816","article-title":"Cabozantinib in Thyroid Cancer","volume":"10","author":"Fallahi","year":"2015","journal-title":"Recent Pat. Anti-Cancer Drug Discov."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"106055","DOI":"10.1016\/j.phrs.2021.106055","article-title":"Polypharmacology: The Science of Multi-Targeting Molecules","volume":"176","author":"Kabir","year":"2022","journal-title":"Pharmacol. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1515\/znc-2019-0160","article-title":"The Application of Essential Oils as a Next-Generation of Pesticides: Recent Developments and Future Perspectives","volume":"75","author":"Fierascu","year":"2020","journal-title":"Z. F\u00fcr Nat. C"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1111\/j.1364-3703.2011.00783.x","article-title":"The Top 10 Fungal Pathogens in Molecular Plant Pathology: Top 10 Fungal Pathogens","volume":"13","author":"Dean","year":"2012","journal-title":"Mol. Plant Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1002\/mbo3.140","article-title":"The Rhizosphere Microbial Community in a Multiple Parallel Mineralization System Suppresses the Pathogenic Fungus Fusarium oxysporum","volume":"2","author":"Fujiwara","year":"2013","journal-title":"MicrobiologyOpen"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"13178","DOI":"10.1038\/s41598-021-92679-x","article-title":"Cytotoxicity Screening of Thymus Vulgaris L. Essential Oil in Brine Shrimp Nauplii and Cancer Cell Lines","volume":"11","author":"Niksic","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1177\/009286159803200223","article-title":"The Use of Biological Assays to Evaluate Botanicals","volume":"32","author":"Mclaughlin","year":"1998","journal-title":"Drug Inf. J."},{"key":"ref_26","first-page":"10","article-title":"Ensayo de Artemia: \u00datil herramienta de trabajo para ecotoxic\u00f3logos y qu\u00edmicos de productos naturales","volume":"25","author":"Lazo","year":"2010","journal-title":"Rev. Protecci\u00f3n Veg."},{"key":"ref_27","first-page":"1059","article-title":"Study the Effect of Carvacrol, Eugenol and Thymol on Fusariums Sp Responsible for Lolium Perenne Fusariosis","volume":"26","author":"Saghrouchni","year":"2020","journal-title":"Ecol. Environ. Conserv. Pap."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"21139","DOI":"10.1038\/s41598-020-77605-x","article-title":"Evaluation of Spore Inoculum and Confirmation of Pathway Genetic Blueprint of T13\u03b1H and DBAT from a Taxol-Producing Endophytic Fungus","volume":"10","author":"Chakravarthi","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Choub, V., Ajuna, H.B., Won, S.-J., Moon, J.-H., Choi, S.-I., Maung, C.E.H., Kim, C.-W., and Ahn, Y.S. (2021). Antifungal Activity of Bacillus Velezensis CE 100 against Anthracnose Disease (Colletotrichum Gloeosporioides) and Growth Promotion of Walnut (Juglans regia L.) Trees. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910438"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1055\/s-2007-971236","article-title":"Brine Shrimp: A Convenient General Bioassay for Active Plant Constituents","volume":"45","author":"Meyer","year":"1982","journal-title":"Planta Med."},{"key":"ref_31","unstructured":"Waghulde, S., Kale, M.K., and Patil, V. (December, January 15). Brine Shrimp Lethality Assay of the Aqueous and Ethanolic Extracts of the Selected Species of Medicinal Plants. Proceedings of the 23rd International Electronic Conference on Synthetic Organic Chemistry, Online."},{"key":"ref_32","first-page":"412","article-title":"Synthesis, Larvicidal and Acetylcholinesterase Inhibitory Activities of Carvacrol\/Thymol and Derivatives","volume":"41","author":"Mesquita","year":"2018","journal-title":"Quim. Nova"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2480","DOI":"10.1016\/j.tetlet.2011.03.017","article-title":"Palladium\/NHC-Catalyzed Oxidative Esterification of Aldehydes with Phenols","volume":"52","author":"Zhang","year":"2011","journal-title":"Tetrahedron Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5622","DOI":"10.1021\/acs.orglett.8b02323","article-title":"Transition-Metal-Free Esterification of Amides via Selective N\u2013C Cleavage under Mild Conditions","volume":"20","author":"Li","year":"2018","journal-title":"Org. Lett."},{"key":"ref_35","first-page":"1931","article-title":"Preparation, Spectral Characterization and Anticancer Potential of Cinnamic Esters","volume":"32","author":"Silva","year":"2021","journal-title":"J. Braz. Chem. Soc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.3390\/molecules19021394","article-title":"Antileishmanial Lead Structures from Nature: Analysis of Structure-Activity Relationships of a Compound Library Derived from Caffeic Acid Bornyl Ester","volume":"19","author":"Glaser","year":"2014","journal-title":"Molecules"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"603","DOI":"10.3184\/030823403322655761","article-title":"Useful Synthesis of Aryl Cinnamates: Synthesis of Difengpin","volume":"10","author":"Mali","year":"2003","journal-title":"J. Chem. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1942","DOI":"10.1080\/07391102.2020.1834455","article-title":"Molecular Networking Based Dereplication of AChE Inhibitory Compounds from the Medicinal Plant Vincetoxicum funebre (Boiss. & Kotschy)","volume":"40","author":"Salehi","year":"2022","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_39","unstructured":"Juan, V.S., Torres, J., Fernando, L., Omar, S.M., Cristina, C.A., and Mar\u00eda del Mar, C.P. (2023). Procedimiento de S\u00edntesis Biol\u00f3gica de Mol\u00e9culas Hibridas. (P202330030), ES Patent."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.jpha.2015.11.005","article-title":"Methods for in Vitro Evaluating Antimicrobial Activity: A Review","volume":"6","author":"Balouiri","year":"2016","journal-title":"J. Pharm. Anal."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.jep.2004.02.011","article-title":"In Vitro Antiplasmodial Activity of Medicinal Plants Native to or Naturalised in South Africa","volume":"92","author":"Clarkson","year":"2004","journal-title":"J. Ethnopharmacol."},{"key":"ref_42","unstructured":"Fetting, C. (2020). The European Green Deal, ESDN Office."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6250","DOI":"10.1016\/j.bmc.2014.08.020","article-title":"Thymol and Eugenol Derivatives as Potential Antileishmanial Agents","volume":"22","author":"Bevilaqua","year":"2014","journal-title":"Bioorganic Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1002\/ps.6678","article-title":"Insecticidal and Growth Inhibitory Effects of Some Thymol Derivatives on the Beet Armyworm, Spodoptera exigua (Lepidoptera: Noctuidae) and Their Impact on Detoxification Enzymes","volume":"78","author":"Pengsook","year":"2022","journal-title":"Pest Manag. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.foodchem.2016.04.111","article-title":"Antibacterial and Antifungal Activities of Thymol: A Brief Review of the Literature","volume":"210","author":"Marchese","year":"2016","journal-title":"Food Chem."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Nehela, Y., Taha, N.A., Elzaawely, A.A., Xuan, T.D., Amin, M.A., Ahmed, M.E., and El-Nagar, A. (2021). Benzoic Acid and Its Hydroxylated Derivatives Suppress Early Blight of Tomato (Alternaria solani) via the Induction of Salicylic Acid Biosynthesis and Enzymatic and Nonenzymatic Antioxidant Defense Machinery. J. Fungi, 7.","DOI":"10.3390\/jof7080663"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Olea, A., Bravo, A., Mart\u00ednez, R., Thomas, M., Sedan, C., Espinoza, L., Zambrano, E., Carvajal, D., Silva-Moreno, E., and Carrasco, H. (2019). Antifungal Activity of Eugenol Derivatives against Botrytis Cinerea. Molecules, 24.","DOI":"10.3390\/molecules24071239"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Zhou, K., Chen, D., Li, B., Zhang, B., Miao, F., and Zhou, L. (2017). Bioactivity and Structure-Activity Relationship of Cinnamic Acid Esters and Their Derivatives as Potential Antifungal Agents for Plant Protection. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0176189"},{"key":"ref_49","unstructured":"Mawardi, A.L., Siregar, A.R.S. (2021). Proceedings of the 2nd International Conference on Science, Atlantis Press."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2637","DOI":"10.1002\/etc.3603","article-title":"Alternative Approaches to Vertebrate Ecotoxicity Tests in the 21st Century: A Review of Developments over the Last 2 Decades and Current Status","volume":"35","author":"Lillicrap","year":"2016","journal-title":"Environ. Toxicol. Chem."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/13\/2\/499\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:31:15Z","timestamp":1760121075000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/13\/2\/499"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,11]]},"references-count":50,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["life13020499"],"URL":"https:\/\/doi.org\/10.3390\/life13020499","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,11]]}}}