{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:19:07Z","timestamp":1785403147962,"version":"3.56.0"},"reference-count":40,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T00:00:00Z","timestamp":1784937600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012996","name":"University of Cyprus","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100012996","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/02qjrjx09","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Natural products featuring a direct \u03c3-bond between a cyclic monoterpene and an aromatic moiety provide a vast source of biological activities, such as antimicrobial, anticancer, antiviral, anticoagulant and cannabinoid regulatory, among others. Only few methods exist for synthetically accessing such hybrid structures and their analogs, all of which are prone to limitations, most notably the reliance on sensitive organometallic intermediates and the difficulty in furnishing certain stereoisomers. An efficient, three-stage synthetic methodology is described herein, that enables the production of hybrid structures featuring a C(sp3)-C(sp2) bond between six-membered cyclic monoterpenes and aromatic moieties. This process combines: enol triflate formation from a terpenoid ketone precursor, that introduces most of the stereochemical information; Suzuki\u2013Miyaura C-C cross-coupling of the enol triflate with a pool of (hetero)arylboronic acids, to establish the terpene\u2013aromatic link, initially in the form of a C(sp2)-C(sp2) bond; and a stereoselective hydrogenation of the resulting adducts to afford the target compounds, establishing the stereoconfiguration of the last chiral center. Enantiomeric terpenoid scaffolds derived from menthone and trans-tetrahydrocarvone have been combined with six (6) (hetero)arylboronic acids, including medicinally relevant moieties, such as methoxyphenyl, pyridine, quinoline and benzofuran. The power of this method, apart from circumventing the need for in situ-formed sensitive organometallic intermediates, resides in providing access, for the first time, to menthyl- and trans-tetrahydrocarvoneyl-type stereoisomers, that were unattainable by any previously described method. The resulting compound library members exhibit drug-like features, based on the computational assessment of 11 selected physicochemical parameters (molecular weight, polarity, aqueous solubility, degree of unsaturation, conformational flexibility, lipophilicity, BBB permeability, skin permeability, gastrointestinal absorption, P-glycoprotein substrate behavior and Lipinski compatibility), using the platforms SwissADME, ADMETLab 3.0 and pkCSM. A computational docking study employing AutoDock Vina further identified promising candidates for targeting the known binding sites of human cannabinoid receptors CB1 and CB2, with calculated binding affinities comparable to those of established ligands.<\/jats:p>","DOI":"10.3390\/molecules31152599","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:49:27Z","timestamp":1785131367000},"page":"2599","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cyclic Monoterpene\u2013Aromatic Hybrids from Chiral Pool Terpenoid Ketones: Practical Synthetic Methodology for Accessing Them and In Silico Assessment as Cannabinoid Receptor CB1\/CB2 Ligands"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-6690-0562","authenticated-orcid":false,"given":"Vasiliki","family":"Kaikiti","sequence":"first","affiliation":[{"name":"Department of Chemistry, University of Cyprus, 1 Panepistimiou Avenue, Nicosia 2109, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Jaksic","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Cyprus, 1 Panepistimiou Avenue, Nicosia 2109, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8952-2432","authenticated-orcid":false,"given":"Basharat","family":"Ali","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, Khawaja Fareed University of Engineering and Information Technology, Rahim Yar Khan 64200, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6106-9904","authenticated-orcid":false,"given":"Savvas N.","family":"Georgiades","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Cyprus, 1 Panepistimiou Avenue, Nicosia 2109, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"C\u00e2mara, J.S., Perestrelo, R., Ferreira, R., Berenguer, C.V., Pereira, J.A.M., and Castilho, P.C. (2024). Plant-derived terpenoids: A plethora of bioactive compounds with several health functions and industrial applications\u2014A comprehensive overview. Molecules, 29.","DOI":"10.3390\/molecules29163861"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Fan, M., Yuan, S., Li, L., Zheng, J., Zhao, D., Wang, C., Wang, H., Liu, X., and Liu, J. (2023). Application of terpenoid compounds in food and pharmaceutical products. Fermentation, 9.","DOI":"10.3390\/fermentation9020119"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e70039","DOI":"10.1002\/elsc.70039","article-title":"Menthol and its derivatives: Exploring the medical application potential","volume":"25","author":"Zhang","year":"2025","journal-title":"Eng. Life Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"113559","DOI":"10.1016\/j.biopha.2022.113559","article-title":"Peppermint essential oil: Its phytochemistry, biological activity, pharmacological effect and application","volume":"154","author":"Zhao","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Li, Z., Zhang, H., Wang, Y., Li, Y., Li, Q., and Zhang, L. (2022). The distinctive role of menthol in pain and analgesia: Mechanisms, practices, and advances. Front. Mol. Neurosci., 15.","DOI":"10.3389\/fnmol.2022.1006908"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Bouyahya, A., Mechchate, H., Benali, T., Ghchime, R., Charfi, S., Balahbib, A., Burkov, P., Shariati, M.A., Lorenzo, J.M., and Omari, N.E. (2021). Health benefits and pharmacological properties of carvone. Biomolecules, 11.","DOI":"10.3390\/biom11121803"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.3109\/13880209.2015.1103753","article-title":"Biological activity of terpene compounds produced by biotechnological methods","volume":"54","author":"Paduch","year":"2016","journal-title":"Pharm. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1007\/s10787-018-0483-z","article-title":"In vitro anti-inflammatory activity of terpenes via suppression of superoxide and nitric oxide generation and the NF-\u03baB Signalling Pathway","volume":"27","author":"Marques","year":"2019","journal-title":"Inflammopharmacology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"113080","DOI":"10.1016\/j.phytochem.2021.113080","article-title":"Carvone and its pharmacological activities: A systematic review","volume":"196","author":"Pina","year":"2022","journal-title":"Phytochemistry"},{"key":"ref_10","first-page":"5716","article-title":"Comparison of anticancer effects of carvone, carvone-rich essential oils, and chitosan nanoparticles containing each of them","volume":"12","author":"Alipanah","year":"2022","journal-title":"Biointerface Res. Appl. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Muhammad, I., Ibrahim, M.A., Kumarihamy, M., Lambert, J.A., Zhang, J., Mohammad, M.H., Khan, S.I., Pasco, D.S., and Balachandran, P. (2023). Cannabinoid and opioid receptor affinity and modulation of cancer-related signaling pathways of machaeriols and machaeridiols from Machaerium Pers. Molecules, 28.","DOI":"10.3390\/molecules28104162"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"112706","DOI":"10.1016\/j.isci.2025.112706","article-title":"How THC works: Explaining ligand affinity for, and partial agonism of, cannabinoid receptor 1","volume":"28","author":"Meister","year":"2025","journal-title":"iScience"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"890","DOI":"10.7164\/antibiotics.54.890","article-title":"Bisabosquals, novel squalene synthase inhibitors. I. Taxonomy, fermentation, isolation and biological activities","volume":"54","author":"Minagawa","year":"2001","journal-title":"J. Antibiot."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1016\/j.biopha.2017.06.065","article-title":"Anti-colon cancer activity of Murraya koenigii leaves is due to constituent murrayazoline and O-methylmurrayamine A induced mTOR\/AKT downregulation and mitochondrial apoptosis","volume":"93","author":"Arun","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"16536","DOI":"10.1002\/ange.201710777","article-title":"Enantiospecific sp2\u2013sp3 coupling of ortho- and para-phenols with secondary and tertiary boronic esters","volume":"129","author":"Wilson","year":"2017","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1038\/nchem.505","article-title":"Highly diastereoselective C(sp3)\u2013C(sp2) Negishi cross-coupling with 1,2-, 1,3-, and 1,4-substituted cycloalkylzinc compounds","volume":"2","author":"Thaler","year":"2010","journal-title":"Nat. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4778","DOI":"10.1021\/acs.orglett.6b02119","article-title":"Diastereoselective cobalt-mediated cross-couplings of cycloalkyl iodides with alkynyl or (hetero)aryl Grignard reagents","volume":"18","author":"Hammann","year":"2016","journal-title":"Org. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e202200906","DOI":"10.1002\/cssc.202200906","article-title":"\u03b1-Amino radical halogen atom transfer agents for cross-electrophile couplings of distinct organic halides","volume":"15","author":"Tian","year":"2022","journal-title":"ChemSusChem"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1021\/jo026525m","article-title":"Temperature- and time-dependent stereochemical control in thermally induced keto\u2212ene cyclizations","volume":"68","author":"Pedrosa","year":"2003","journal-title":"J. Org. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"11446","DOI":"10.1021\/jacs.9b06231","article-title":"Palladium-catalyzed asymmetric allylic fluoroalkylation\/trifluoromethylation","volume":"141","author":"Trost","year":"2019","journal-title":"J. Am. Chem. Soc."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"17911","DOI":"10.1002\/chem.201804529","article-title":"Dual gold-catalyzed formal tetradehydro-Diels-Alder reactions for the synthesis of carbazoles and indolines","volume":"24","author":"Wang","year":"2018","journal-title":"Chem. Eur. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/S0960-894X(02)00009-4","article-title":"N-Aryl 2,6-dimethoxybiphenylalanine analogues as VLA-4 Antagonists","volume":"12","author":"Doherty","year":"2002","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1016\/S0026-895X(25)09587-2","article-title":"Investigation of the role of the phenolic hydroxyl in cannabinoid activity","volume":"38","author":"Reggio","year":"1990","journal-title":"Mol. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"15385","DOI":"10.1039\/D2RA01571D","article-title":"Pyridine: The scaffolds with significant clinical diversity","volume":"12","author":"De","year":"2022","journal-title":"RSC Adv."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"104639","DOI":"10.1016\/j.bioorg.2021.104639","article-title":"Quinolines, a perpetual, multipurpose scaffold in medicinal chemistry","volume":"109","author":"Yadav","year":"2021","journal-title":"Bioorg. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"96809","DOI":"10.1039\/C5RA20658H","article-title":"Benzofuran: An emerging scaffold for antimicrobial agents","volume":"5","author":"Hiremathad","year":"2015","journal-title":"RSC Adv."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1021\/acsinfecdis.3c00154","article-title":"Exploring the antibacterial potential of semisynthetic phytocannabinoid: Tetrahydrocannabidiol (THCBD) as a potential antibacterial agent against sensitive and resistants of Staphylococcus aureus","volume":"10","author":"Cham","year":"2024","journal-title":"ACS Infect. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2858","DOI":"10.1021\/acs.jnatprod.1c00567","article-title":"Photochemistry of cannabidiol (CBD) revised. A combined preparative and spectrometric investigation","volume":"84","author":"Seccamani","year":"2021","journal-title":"J. Nat. Prod."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2783","DOI":"10.1039\/D5CY00118H","article-title":"Catalytic static mixers enable the continuous hydrogenation of cannabidiol and tetrahydrocannabinol","volume":"15","author":"Martinuzzi","year":"2025","journal-title":"Catal. Sci. Technol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Kumarihamy, M., Tripathi, S., Balachandran, P., Avula, B., Zhao, J., Wang, M., Bennett, M.M., Zhang, J., Carr, M.A., and Lovell, K.M. (2022). Synthesis and inhibitory activity of machaeridiol-based novel anti-MRSA and anti-VRE compounds and their profiling for cancer-related signaling pathways. Molecules, 27.","DOI":"10.3390\/molecules27196604"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4512","DOI":"10.1002\/anie.201411882","article-title":"Catalytic asymmetric hydroalkenylation of vinylarenes: Electronic effects of substrates and chiral N-heterocyclic carbene ligands","volume":"54","author":"Ho","year":"2015","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"14102","DOI":"10.1021\/acscatal.1c04239","article-title":"Ni-Catalyzed formal cross-electrophile coupling of alcohols with aryl halides","volume":"11","author":"Lin","year":"2021","journal-title":"ACS Catal."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2870","DOI":"10.1021\/ja00901a059","article-title":"Vicinal proton coupling in nuclear magnetic resonance","volume":"85","author":"Karplus","year":"1963","journal-title":"J. Am. Chem. Soc."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"W357","DOI":"10.1093\/nar\/gkz382","article-title":"SwissTargetPrediction: Updated data and new features for efficient prediction of protein targets of small molecules","volume":"47","author":"Daina","year":"2019","journal-title":"Nucl. Acids Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"W422","DOI":"10.1093\/nar\/gkae236","article-title":"ADMETlab 3.0: An updated comprehensive online ADMET prediction platform enhanced with broader coverage, improved performance, API functionality and decision support","volume":"52","author":"Fu","year":"2024","journal-title":"Nucl. Acids Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4066","DOI":"10.1021\/acs.jmedchem.5b00104","article-title":"pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures","volume":"58","author":"Pires","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"107590","DOI":"10.1016\/j.compbiolchem.2021.107590","article-title":"Virtual screening using docking and molecular dynamics of cannabinoid analogs against CB1 and CB2 receptors","volume":"95","year":"2021","journal-title":"Comp. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1016\/j.cell.2016.10.004","article-title":"Crystal structure of the human cannabinoid receptor CB1","volume":"167","author":"Hua","year":"2016","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.cell.2018.12.011","article-title":"Crystal structure of the human cannabinoid receptor CB2","volume":"176","author":"Li","year":"2019","journal-title":"Cell"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/15\/2599\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T04:15:51Z","timestamp":1785212151000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/15\/2599"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,25]]},"references-count":40,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["molecules31152599"],"URL":"https:\/\/doi.org\/10.3390\/molecules31152599","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,25]]}}}