{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T09:14:06Z","timestamp":1779095646001,"version":"3.51.4"},"reference-count":48,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,17]],"date-time":"2026-05-17T00:00:00Z","timestamp":1778976000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical Science Council (SMN) at MU-Sofia","award":["147\/29.05.2024"],"award-info":[{"award-number":["147\/29.05.2024"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>(1) Background: Cinnamaldehyde exhibits a broad spectrum of biological activities, and its \u03b1,\u03b2-unsaturated aldehyde scaffold serves as a versatile platform for the design of hydrazone derivatives with improved pharmacological properties. (2) Methods: In this study, eight cinnamaldehyde-based hydrazones were synthesized via a one-step condensation reaction between cinnamaldehyde and para-substituted acylhydrazides. Prior to synthesis, an in silico assessment of physicochemical, pharmacokinetic, ADME (absorption, distribution, metabolism, elimination), lead-likeness, and drug-likeness properties was conducted using SwissADME, ACD\/Labs v. 9.10, and MDL QSAR v2.2.0.0.446 software. Structural characterization by IR, 1H NMR, 13C NMR, and HR ESI\u2013MS confirmed successful formation of the hydrazone linkage. Cytotoxic activity was evaluated using the MTT assay against selected cancer cell lines. (3) Results: All compounds exhibited favorable lead-like characteristics, including suitable molecular weight, moderate lipophilicity, and acceptable predicted ADME profiles. Biological evaluation revealed moderate, structure-dependent antiproliferative activity with clear cell line selectivity. Among the series, compound CA8 showed the most promising profile, displaying the highest cytotoxic activity against T-cell leukemia KE-37 cells (IC50 = 20.3 \u00b1 2.8 \u03bcM), comparable to reference drug melphalan (IC50 = 21.40 \u00b1 3.9 \u03bcM), and the highest selectivity index (\u226519.7). Structure\u2013activity analysis suggests that an amino substituent enhances both potency and selectivity. (4) Conclusions: Overall, these findings identify cinnamaldehyde hydrazones as a promising scaffold for anticancer drug development and provide a strong basis for further structural optimization.<\/jats:p>","DOI":"10.3390\/molecules31101701","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T08:56:27Z","timestamp":1779094587000},"page":"1701","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel Cinnamaldehyde Hydrazones: Design, In Silico Evaluation, Synthesis, and Cytotoxic Activity"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0440-9247","authenticated-orcid":false,"given":"Boryana","family":"Nikolova-Mladenova","sequence":"first","affiliation":[{"name":"Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5763-0730","authenticated-orcid":false,"given":"Rositsa","family":"Mihaylova","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9761-0355","authenticated-orcid":false,"given":"Mariyana","family":"Atanasova","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria"},{"name":"Centre of Excellence in Informatics and Information and Communication Technologies, Bulgarian Academy of Sciences, Akad. Georgi Bonchev Str., Block 2 and 25A, 1113 Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Karimirad, R., Inbaraj, B.S., and Chen, B.-H. (2025). Recent Advances on the Analysis and Biological Functions of Cinnamaldehyde and Its Derivatives. Antioxidants, 14.","DOI":"10.3390\/antiox14070765"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"9755061","DOI":"10.1155\/joch\/9755061","article-title":"Evaluation of Antioxidant and Enzyme Inhibitory Properties of Cinnamaldehyde: In Vitro and In Silico Investigations","volume":"2026","author":"Touhtouh","year":"2026","journal-title":"J. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.22214\/ijraset.2022.47606","article-title":"Antioxidant and Antibacterial Activity of Cinnamaldehyde Derivative","volume":"10","author":"Anzam","year":"2022","journal-title":"Int. J. Res. Appl. Sci. Eng. Technol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1034325","DOI":"10.1155\/2020\/1034325","article-title":"Natural Cinnamaldehyde and Its Derivatives Ameliorate Neuroinflammatory Pathways in Neurodegenerative Diseases","volume":"2020","author":"Hajinejad","year":"2020","journal-title":"BioMed Res. Int."},{"key":"ref_5","first-page":"271","article-title":"The neuroprotective mechanism of cinnamaldehyde against amyloid-\u03b2 in neuronal SHSY5Y cell line: The role of N-methyl-D-aspartate, ryanodine, and adenosine receptors and glycogen synthase kinase-3\u03b2","volume":"9","author":"Emamghoreishi","year":"2019","journal-title":"Avicenna J. Phytomed."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e392","DOI":"10.1016\/j.wneu.2021.06.117","article-title":"Neuroprotective Effect of Cinnamaldehyde on Secondary Brain Injury After Traumatic Brain Injury in a Rat Model","volume":"153","author":"Demir","year":"2021","journal-title":"World Neurosurg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.fct.2007.07.016","article-title":"Cinnamaldehyde inhibits pro-inflammatory cytokines secretion from monocytes\/macrophages through suppression of intracellular signaling","volume":"46","author":"Chao","year":"2008","journal-title":"Food Chem. Toxicol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s10522-007-9098-2","article-title":"Suppression of age-related inflammatory NF-kappaB activation by cinnamaldehyde","volume":"8","author":"Kim","year":"2007","journal-title":"Biogerontology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10406","DOI":"10.1021\/acs.jafc.7b04344","article-title":"Chemistry, Antimicrobial Mechanisms, and Antibiotic Activities of Cinnamaldehyde against Pathogenic Bacteria in Animal Feeds and Human Foods","volume":"65","author":"Friedman","year":"2017","journal-title":"J. Agric. Food Chem."},{"key":"ref_10","first-page":"263","article-title":"Sources, extraction and biological activities of cinnamaldehyde","volume":"8","author":"Ibi","year":"2022","journal-title":"Trends Pharm. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.fitote.2016.05.016","article-title":"Cinnamaldehyde and its derivatives, a novel class of antifungal agents","volume":"112","author":"Shreaz","year":"2016","journal-title":"Fitoterapia"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"104405","DOI":"10.1016\/j.fitote.2019.104405","article-title":"A review of cinnamaldehyde and its derivatives as antibacterial agents","volume":"139","author":"Doyle","year":"2019","journal-title":"Fitoterapia"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1007\/s11130-019-00760-8","article-title":"Cinnamon Shows Antidiabetic Properties that Are Species-Specific: Effects on Enzyme Activity Inhibition and Starch Digestion","volume":"74","author":"Hayward","year":"2019","journal-title":"Plant Foods Hum. Nutr."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Jaramillo Jimenez, B.A., Awwad, F., and Desgagn\u00e9-Penix, I. (2024). Cinnamaldehyde in Focus: Antimicrobial Properties, Biosynthetic Pathway, and Industrial Applications. Antibiotics, 13.","DOI":"10.3390\/antibiotics13111095"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.phrs.2017.05.019","article-title":"Cinnamaldehyde in diabetes: A review of pharmacology, pharmacokinetics and safety","volume":"122","author":"Zhu","year":"2017","journal-title":"Pharmacol. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"173","DOI":"10.3390\/physiologia3020013","article-title":"Anticancer Potential and Molecular Mechanisms of Cinnamaldehyde and Its Congeners Present in the Cinnamon Plant","volume":"3","author":"Banerjee","year":"2023","journal-title":"Physiologia"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"163","DOI":"10.3892\/mmr.2024.13287","article-title":"Cinnamaldehyde: Pharmacokinetics, anticancer properties and therapeutic potential (Review)","volume":"30","author":"Han","year":"2024","journal-title":"Mol. Med. Rep."},{"key":"ref_18","first-page":"140","article-title":"The role and mechanism of cinnamaldehyde in cancer","volume":"32","author":"Peng","year":"2024","journal-title":"J. Food Drug Anal."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.3109\/13880200903019242","article-title":"Comparative analysis of cytotoxic effect of aqueous cinnamon extract from Cinnamomum zeylanicum bark with commercial cinnamaldehyde on various cell lines","volume":"47","author":"Singh","year":"2009","journal-title":"Pharm. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Al Nasr, I.S., Koko, W.S., Khan, T.A., Schobert, R., and Biersack, B. (2024). Antiparasitic Activities of Acyl Hydrazones from Cinnamaldehydes and Structurally Related Fragrances. Antibiotics, 13.","DOI":"10.3390\/antibiotics13121114"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.phytol.2024.11.010","article-title":"Design, synthesis, and antifungal activity of hydrazone Schiff bases containing cinnamaldehyde moieties","volume":"65","author":"Yang","year":"2025","journal-title":"Phytochem. Lett."},{"key":"ref_22","first-page":"51","article-title":"Synthesis and spectropic characterization of schiff base complexes of cinnamaldehyde hydrazones","volume":"3","author":"Salawu","year":"2011","journal-title":"J. Phys. Sci. Innov."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"136654","DOI":"10.1016\/j.ijbiomac.2024.136654","article-title":"Preferential inhibition of \u03b1-amylase by cinnamaldehyde-based hydrazones: A comparative study","volume":"281","author":"Vashisth","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"132684","DOI":"10.1016\/j.ijbiomac.2024.132684","article-title":"Cinnamaldehyde hydrazone derivatives as potential cathepsin B inhibitors: Parallel in-vitro investigation in liver and cerebrospinal fluid","volume":"272","author":"Vashisth","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_25","first-page":"217","article-title":"Hydrazones derived from natural aldehydes: In vitro cytotoxic evaluation and in silico pharmacokinetic predictions","volume":"50","author":"Pessoa","year":"2021","journal-title":"Rev. Colomb. Cienc. Qu\u00edm. Farm."},{"key":"ref_26","first-page":"100036","article-title":"Pyrrolizine\/indolizine-cinnamaldehyde Schiff bases: Design, synthesis, biological evaluation, ADME, and molecular docking study","volume":"4","author":"Abourehab","year":"2022","journal-title":"Eur. J. Med. Chem. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"art236087","DOI":"10.32371\/jtmc\/236087","article-title":"Schiff Bases and their Copper(II) Complexes Derived from Cinnamaldehyde and Different Hydrazides: Synthesis and Antibacterial Properties","volume":"3","author":"Khor","year":"2020","journal-title":"J. Transit. Met. Complexes."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"30627","DOI":"10.1039\/D5RA03706A","article-title":"Design, synthesis, and in silico docking studies of novel cinnamaldehyde\u2013chalcone derivatives with anti-cancer potential and in vivo acute oral toxicity profiling","volume":"15","author":"Soumya","year":"2025","journal-title":"RSC Adv."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1002\/jps.22819","article-title":"Prediction of Steady-State Volume of Distribution of Acidic Drugs by Quantitative Structure\u2013Pharmacokinetics Relationships","volume":"101","author":"Zhivkova","year":"2012","journal-title":"J. Pharm. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4627","DOI":"10.1002\/jps.23303","article-title":"Quantitative structure\u2014Plasma protein binding relationships of acidic drugs","volume":"101","author":"Zhivkova","year":"2012","journal-title":"J. Pharm. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3758","DOI":"10.1021\/mp400251k","article-title":"Quantitative Structure\u2014Clearance Relationships of Acidic Drugs","volume":"10","author":"Zhivkova","year":"2013","journal-title":"Mol. Pharm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.ddtec.2004.11.007","article-title":"Lead- and drug-like compounds: The rule-of-five revolution","volume":"1","author":"Lipinski","year":"2004","journal-title":"Drug Discov. Today Technol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1023\/A:1015040217741","article-title":"Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs","volume":"16","author":"Kelder","year":"1999","journal-title":"Pharm. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.2174\/15680266113139990035","article-title":"Permeability Diagnosis Model in Drug Discovery: A Diagnostic Tool to Identify the Most Influencing Properties for Gastrointestinal Permeability","volume":"13","author":"Wang","year":"2013","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1023\/A:1012188625088","article-title":"Polar molecular surface properties predict the intestinal absorption of drugs in humans","volume":"14","author":"Palm","year":"1997","journal-title":"Pharm. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1021\/acs.jmedchem.7b00237","article-title":"How Big Is Too Big for Cell Permeability?","volume":"60","author":"Matsson","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1602\/neurorx.2.4.541","article-title":"Medicinal chemical properties of successful central nervous system drugs","volume":"2","author":"Pajouhesh","year":"2005","journal-title":"NeuroRx"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"7559","DOI":"10.1021\/jm060642i","article-title":"Structure-brain exposure relationships","volume":"49","author":"Hitchcock","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3743","DOI":"10.1002\/(SICI)1521-3773(19991216)38:24<3743::AID-ANIE3743>3.0.CO;2-U","article-title":"The Design of Leadlike Combinatorial Libraries","volume":"38","author":"Teague","year":"1999","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.jmb.2005.07.075","article-title":"Structural Basis of the Drug-binding Specificity of Human Serum Albumin","volume":"353","author":"Ghuman","year":"2005","journal-title":"J. Mol. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2069","DOI":"10.1021\/ci300155y","article-title":"In silico Prediction of Total Human Plasma Clearance","volume":"52","author":"Berellini","year":"2012","journal-title":"J. Chem. Inf. Model."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.jab.2017.04.004","article-title":"Design and drug-like properties of new 5-methoxysalicylaldehyde based hydrazones with anti-breast cancer activity","volume":"15","author":"Momekov","year":"2017","journal-title":"J. Appl. Biomed."},{"key":"ref_43","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_44","doi-asserted-by":"crossref","unstructured":"Nikolova-Mladenova, B., Mihaylova, R., Atanasova, M., Zhivkova, Z., and Doytchinova, I. (2025). Salicylaldehyde Benzoylhydrazones with Anticancer Activity and Selectivity: Design, Synthesis, and In Vitro Evaluation. Molecules, 30.","DOI":"10.3390\/molecules30051015"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.bbagen.2008.04.003","article-title":"Cancer cell iron metabolism and the development of potent iron chelators as anti-tumour agents","volume":"1790","author":"Richardson","year":"2009","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1910","DOI":"10.3390\/12081910","article-title":"Biological Activities of Hydrazone Derivatives","volume":"12","author":"Rollas","year":"2007","journal-title":"Molecules"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s10534-020-00243-3","article-title":"Iron chelators in cancer therapy","volume":"33","author":"Ibrahim","year":"2020","journal-title":"Biometals"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"J. Immunol. Methods"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/10\/1701\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T09:00:30Z","timestamp":1779094830000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/10\/1701"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,17]]},"references-count":48,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["molecules31101701"],"URL":"https:\/\/doi.org\/10.3390\/molecules31101701","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,17]]}}}