{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:15:50Z","timestamp":1788412550542,"version":"build-2803163510"},"reference-count":36,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010621","name":"Medical University of Lublin","doi-asserted-by":"crossref","award":["DS14"],"award-info":[{"award-number":["DS14"]}],"id":[{"id":"10.13039\/501100010621","id-type":"DOI","asserted-by":"crossref"}]},{"award":["DS14"],"award-info":[{"award-number":["DS14"]}],"id":[{"id":"https:\/\/ror.org\/016f61126","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Background\/Objectives: The rapid emergence of antimicrobial resistance has created an urgent need for new chemotypes with activity against bacterial, fungal, and mycobacterial pathogens. Rhodanine-based compounds are recognized as privileged scaffolds in medicinal chemistry because of their broad spectrum of biological activities, making them attractive candidates for the development of novel antimicrobial agents. Methods: A library of thirty-two novel rhodanine-based hydrazide derivatives (21\u201352) was synthesized by condensation of 5-ethoxymethylidenerhodanine derivatives with aromatic acid hydrazides and characterized by IR, 1H NMR, and 13C NMR spectroscopy. Their drug-likeness and pharmacokinetics properties were evaluated using SwissADME, while antimicrobial activity was assessed against Gram-positive and Gram-negative bacteria, Candida spp., and both drug-susceptible and drug-resistant Mycobacterium tuberculosis strains using minimum inhibitory concentration (MIC) assays. Results: The synthesized compounds demonstrated selective activity against Gram-positive bacteria, whereas only limited activity was observed against Gram-negative species. The most potent derivatives (36, 40, 46, and 50) inhibited Micrococcus luteus with MIC values as low as 31.3 mg\/L. Several compounds also demonstrated noteworthy antifungal activity, particularly against Candida parapsilosis (MIC = 15.6\u201331.3 \u00b5g\/mL). Pyridyl-containing analogues displayed moderate antitubercular activity and, importantly, compounds 49 and 52 retaining activity against both drug-susceptible and drug-resistant M. tuberculosis strains. In silico analysis indicated favorable drug-like properties for most compounds, with good compliance with Lipinski\u2019s rule of five and predicted oral bioavailability. Preliminary structure\u2013activity relationship analysis revealed that a 3-phenylrhodanine core combined with para-halogen or para-nitro substituents significantly enhanced antimicrobial potency. Conclusions: The present study identifies rhodanine-based hydrazide derivatives as promising multifunctional antimicrobial scaffolds with activity against Gram-positive bacteria, pathogenic yeasts, and M. tuberculosis. The identified structure\u2013activity relationships provide a rational basis for further lead optimization and support continued development of this chemotype as a potential source of new antimicrobial agents.<\/jats:p>","DOI":"10.3390\/antibiotics15090853","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T10:32:18Z","timestamp":1788258738000},"page":"853","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, Synthesis and Biological Evaluation of Rhodanine-Based Hydrazide Derivatives as Antibacterial, Antifungal, and Antitubercular Agents"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8198-7702","authenticated-orcid":false,"given":"Agata","family":"Paneth","sequence":"first","affiliation":[{"name":"Department of Organic Chemistry, Medical University of Lublin, Chodzki 4A, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1634-0387","authenticated-orcid":false,"given":"Izabela","family":"Korona-G\u0142owniak","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Microbiology, Medical University in Lublin, Chodzki 1, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1296-4934","authenticated-orcid":false,"given":"Agnieszka","family":"G\u0142ogowska","sequence":"additional","affiliation":[{"name":"Department of Microbiology, National Tuberculosis and Lung Diseases Research Institute, Plocka 26, 01-138 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0383-4855","authenticated-orcid":false,"given":"Jacek","family":"Szczepa\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Medical University of Lublin, Chodzki 4A, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Dominik","family":"W\u0142odarczyk","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Medical University of Lublin, Chodzki 4A, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1360-5901","authenticated-orcid":false,"given":"Katarzyna","family":"Su\u015bniak","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Microbiology, Medical University in Lublin, Chodzki 1, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6162-8748","authenticated-orcid":false,"given":"Ewa","family":"Augustynowicz-Kope\u0107","sequence":"additional","affiliation":[{"name":"Department of Microbiology, National Tuberculosis and Lung Diseases Research Institute, Plocka 26, 01-138 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8817-7470","authenticated-orcid":false,"given":"Nazar","family":"Trotsko","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Medical University of Lublin, Chodzki 4A, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/S0140-6736(21)02724-0","article-title":"Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis","volume":"399","author":"Murray","year":"2022","journal-title":"Lancet"},{"key":"ref_2","unstructured":"World Health Organization (2025). Global Antibiotic Resistance Surveillance Report 2025: WHO Global Antimicrobial Resistance and Use Surveillance System (GLASS), World Health Organization."},{"key":"ref_3","unstructured":"WHO Regional Office for Europe (2025). WHO Regional Office for Europe and European Centre for Disease Prevention and Control. Surveillance of Antimicrobial Resistance in Europe, 2024 Data: Executive Summary, WHO Regional Office for Europe."},{"key":"ref_4","first-page":"277","article-title":"The antibiotic resistance crisis: Part 1: Causes and threats","volume":"40","author":"Ventola","year":"2015","journal-title":"Pharmacol. Ther."},{"key":"ref_5","unstructured":"Centers for Disease Control and Prevention (2019). Antibiotic Resistance Threats in the United States, CDC."},{"key":"ref_6","unstructured":"World Health Organization (2024). WHO Bacterial Priority Pathogens List, 2024: Bacterial Pathogens of Public Health Importance to Guide Research, Development and Strategies to Prevent and Control Antimicrobial Resistance, World Health Organization."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/S1473-3099(17)30753-3","article-title":"Discovery, research, and development of new antibiotics: The WHO priority list of antibiotic-resistant bacteria","volume":"18","author":"Tacconelli","year":"2018","journal-title":"Lancet Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.cell.2020.02.056","article-title":"The Science of Antibiotic Discovery","volume":"181","author":"Lewis","year":"2020","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1038\/s41570-021-00313-1","article-title":"Towards the sustainable discovery and development of new antibiotics","volume":"5","author":"Miethke","year":"2021","journal-title":"Nat. Rev. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1517\/17460441.2012.688743","article-title":"Rhodanine as a Scaffold in Drug Discovery: A Critical Review of Its Biological Activities and Mechanisms of Target Modulation","volume":"7","year":"2012","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1080\/17460441.2017.1388370","article-title":"Recent Developments with Rhodanine as a Scaffold for Drug Discovery","volume":"12","author":"Kaminskyy","year":"2017","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Szczepa\u0144ski, J., Tuszewska, H., and Trotsko, N. (2022). Anticancer Profile of Rhodanines: Structure\u2013Activity Relationship (SAR) and Molecular Targets\u2014A Review. Molecules, 27.","DOI":"10.3390\/molecules27123750"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"112406","DOI":"10.1016\/j.biopha.2021.112406","article-title":"Review of Anticancer Potentials and Structure\u2013Activity Relationships (SAR) of Rhodanine Derivatives","volume":"145","author":"Yin","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"100131","DOI":"10.1016\/j.medidd.2022.100131","article-title":"Rhodanine Scaffold: A Review of Antidiabetic Potential and Structure\u2013Activity Relationships (SAR)","volume":"15","author":"Yin","year":"2022","journal-title":"Med. Drug Discov."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1111\/cbdd.14163","article-title":"Rhodanine Derivatives: An Insight into the Synthetic and Medicinal Perspectives as Antimicrobial and Antiviral Agents","volume":"101","author":"Chaurasyia","year":"2023","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e22113525295259","DOI":"10.2174\/0122113525295259240815073809","article-title":"A Comprehensive Review on the Antimicrobial Activities and Structure\u2013Activity Relationships (SARs) of Rhodanine Analogues","volume":"23","author":"Fung","year":"2025","journal-title":"Anti-Infect. Agents"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e202200213","DOI":"10.1002\/cbdv.202200213","article-title":"Synthesis and antibacterial evaluation of rhodanine and its related heterocyclic compounds against S. aureus and A. baumannii","volume":"19","author":"Akunuri","year":"2022","journal-title":"Chem. Biodivers."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1016\/j.jsps.2018.01.016","article-title":"Synthesis and antibacterial activity of new (2,4-dioxothiazolidin-5-yl\/ylidene)acetic acid derivatives with thiazolidine-2,4-dione, rhodanine and 2-thiohydantoin moieties","volume":"26","author":"Trotsko","year":"2018","journal-title":"Saudi Pharm. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1007\/s00044-017-1852-7","article-title":"Antibacterial properties of 5-substituted derivatives of rhodanine-3-carboxyalkyl acids","volume":"26","author":"Tejchman","year":"2017","journal-title":"Med. Chem. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e202201007","DOI":"10.1002\/slct.202201007","article-title":"Quinolone-rhodanine hybrid compounds: Synthesis and biological evaluation as anti-bacterial agents","volume":"7","author":"Cebeci","year":"2022","journal-title":"ChemistrySelect"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"118545","DOI":"10.1016\/j.bmc.2026.118545","article-title":"Synthesis and evaluation of novel 4-thiazolidinone-5-nitrofuran hybrids as promising antimicrobial agents","volume":"134","author":"Horishny","year":"2026","journal-title":"Bioorg. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e2400064","DOI":"10.1002\/ardp.202400064","article-title":"Exploring rhodanine linked enamine-carbohydrazide derivatives as mycobacterial carbonic anhydrase inhibitors: Design, synthesis, biological evaluation, and molecular docking studies","volume":"357","author":"Maddipatla","year":"2024","journal-title":"Arch. Pharm."},{"key":"ref_23","first-page":"2601","article-title":"Synthesis of thiocyanic acid","volume":"32","author":"Grishchuk","year":"1959","journal-title":"Zh. Prikl. Khimii"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5197","DOI":"10.1016\/j.tetlet.2012.07.002","article-title":"Aqueous microwave-assisted one-pot synthesis of N-substituted rhodanines","volume":"53","author":"Nitsche","year":"2012","journal-title":"Tetrahedron Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4166","DOI":"10.1021\/ja01645a033","article-title":"5-Alkoxymethylenerhodanines and their reactions with rhodanines","volume":"76","author":"Lo","year":"1954","journal-title":"J. Am. Chem. Soc."},{"key":"ref_26","unstructured":"Mazurkiewicz, R., Rajca, A., Salwi\u0144ska, E., Skibi\u0144ski, A., Suwi\u0144ski, J., and Zieli\u0144ski, W. (2000). Metody Spektroskopowe i ich Zastosowanie do Identyfikacji Zwi\u0105zk\u00f3w Organicznych, Wydawnictwo Naukowo-Techniczne. (In Polish)."},{"key":"ref_27","unstructured":"(2026, June 24). Available online: http:\/\/www.swissadme.ch\/index.php."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(00)00129-0","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"46","author":"Lipinski","year":"2001","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3164","DOI":"10.1021\/jm0492002","article-title":"A bioavailability score","volume":"48","author":"Martin","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.ejmech.2017.04.002","article-title":"Isoniazid derivatives and their anti-tubercular activity","volume":"133","author":"Hu","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.ebiom.2019.10.014","article-title":"Impact of the most environment on the antitubercular action of pyrazinamide","volume":"49","author":"Lamont","year":"2019","journal-title":"EBioMedicine"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_33","unstructured":"(2024). Susceptibility Testing of Mycobacteria, Nocardia spp., and Other Aerobic Actinomycetes (Standard No. CLSI M24)."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"102412","DOI":"10.1016\/j.tube.2023.102412","article-title":"In vitro antimycobacterial activity and interaction profiles of diarylthiourea\u2013copper (ii) complexes with antitubercular drugs against Mycobacterium tuberculosis isolates","volume":"143","author":"Bielenica","year":"2023","journal-title":"Tuberculosis"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1128\/JCM.36.2.362-366.1998","article-title":"Rapid, low-technology MIC determination with clinical Mycobacterium tuberculosis isolates by using the microplate Alamar Blue assay","volume":"36","author":"Franzblau","year":"1998","journal-title":"J. Clin. Microbiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7834","DOI":"10.1021\/jm2008826","article-title":"Novel N-linked aminopiperidine inhibitors of bacterial topoisomerase type II: Broad-spectrum antibacterial agents with reduced hERG activity","volume":"54","author":"Reck","year":"2011","journal-title":"J. Med. Chem."}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/15\/9\/853\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T04:28:32Z","timestamp":1788409712000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/15\/9\/853"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,1]]},"references-count":36,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["antibiotics15090853"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics15090853","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,1]]}}}