{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T13:00:50Z","timestamp":1774270850397,"version":"3.50.1"},"reference-count":37,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,8,24]],"date-time":"2024-08-24T00:00:00Z","timestamp":1724457600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>The rapid emergence and spread of multidrug-resistant microorganisms is threatening our ability to treat common infections, with serious medical, social, and economic consequences. Despite substantial progress in the global fight against antibiotic resistance, the number of effective antibiotics is rapidly decreasing, underlying the urgent need to develop novel antimicrobials. In the present study, the green synthesis of novel iodine-substituted tricyclic flavonoids has been accomplished using an eco-friendly reagent, HPW-SiO2, as a cyclization agent for the precursor 3-dithiocarmamic flavanones. In vitro antimicrobial activity of the new compounds was evaluated using minimum inhibitory concentration (MIC) and minimum bactericidal\/fungicidal concentrations. All tested compounds displayed potent inhibitory activity against all tested microbial strains, with the lowest MIC values of 0.12 \u00b5g\/mL and 0.48 \u00b5g\/mL recorded for compound 5c against Gram-positive bacteria Bacillus subtilis and Staphylococcus aureus. Higher MIC values (7.81 \u00b5g\/mL) were registered for several flavonoids against Gram-negative bacteria Escherichia coli and Acinetobacter pittii. No inhibitory activity was evidenced against Pseudomonas aeruginosa strain. The highest antifungal activity was displayed by flavonoid 5d against Candida krusei (MIC = 3.9 \u00b5g\/mL). The same compound also exhibited the most potent bactericidal and fungicidal activity against Bacillus subtilis (0.9 \u00b5g\/mL) and Staphylococcus aureus (1.97 \u00b5g\/mL), Candida albicans, and Candida krusei (7.81 \u00b5g\/mL). Based on the reported results, we believe that the novel iodine-substituted tricyclic flavonoids have good potential to become new antimicrobial agents effective against bacterial and fungal strains, including WHO-priority pathogens.<\/jats:p>","DOI":"10.3390\/antibiotics13090798","type":"journal-article","created":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T04:48:25Z","timestamp":1724647705000},"page":"798","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["An Eco-Friendly Method to Synthesize Potent Antimicrobial Tricyclic Flavonoids"],"prefix":"10.3390","volume":"13","author":[{"given":"Loredana-Elena","family":"Mantea","sequence":"first","affiliation":[{"name":"Department of Biology, Faculty of Biology, Alexandru Ioan Cuza University of Iasi, Bd. Carol I, No. 11, 700506 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1079-5981","authenticated-orcid":false,"given":"Cristina-Veronica","family":"Moldovan","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Biology, Alexandru Ioan Cuza University of Iasi, Bd. Carol I, No. 11, 700506 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6029-5283","authenticated-orcid":false,"given":"Mihaela","family":"Savu","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Biology, Alexandru Ioan Cuza University of Iasi, Bd. Carol I, No. 11, 700506 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1789-2108","authenticated-orcid":false,"given":"Laura Gabriela","family":"Sarbu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Alexandru Ioan Cuza University of Iasi, No. 11 Carol I Blvd., 700506 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4967-6234","authenticated-orcid":false,"given":"Marius","family":"Stefan","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Biology, Alexandru Ioan Cuza University of Iasi, Bd. Carol I, No. 11, 700506 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4483-873X","authenticated-orcid":false,"given":"Mihail Lucian","family":"Birsa","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Alexandru Ioan Cuza University of Iasi, No. 11 Carol I Blvd., 700506 Iasi, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,24]]},"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","doi-asserted-by":"crossref","unstructured":"Tang, K.W.K., Millar, B.C., and Moore, J.E. (2023). Antimicrobial resistance (AMR). Br. J. Biomed. Sci., 80.","DOI":"10.3389\/bjbs.2023.11387"},{"key":"ref_3","unstructured":"The World Bank (2017). Drug-Resistant Infections: A Threat to Our Economic Future, World Bank."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"735","DOI":"10.2147\/IDR.S345574","article-title":"Clinical perspective of antimicrobial resistance in bacteria","volume":"15","author":"Zhu","year":"2022","journal-title":"Infect. Drug Resist."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e24655","DOI":"10.1002\/jcla.24655","article-title":"Antibiotic resistance: The challenges and some emerging strategies for tackling a global menace","volume":"36","author":"Ugwu","year":"2022","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_6","unstructured":"World Health Organization (2022). Global Antimicrobial Resistance and Use Surveillance System (GLASS) Report 2022, World Health Organization."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e149","DOI":"10.52225\/narra.v3i1.149","article-title":"Distribution and antibacterial susceptibility pattern of isolated bacteria from endotracheal aspirates among ventilator-assisted pneumonia patients in Indonesia","volume":"3","author":"Andayani","year":"2023","journal-title":"Narra J."},{"key":"ref_8","unstructured":"World Health Organization (2024). 2023 Antibacterial Agents in Clinical and Preclinical Development: An Overview and Analysis, World Health Organization."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Ullah, A., Munir, S., Badshah, S.L., Khan, N., Ghani, L., Poulson, B.G., Emwas, A.H., and Jaremko, M. (2020). Important flavonoids and their role as a therapeutic agent. Molecules, 25.","DOI":"10.3390\/molecules25225243"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/s11101-018-9591-z","article-title":"Comprehensive review of antimicrobial activities of plant flavonoids","volume":"18","author":"Bartoszewski","year":"2019","journal-title":"Phytochem. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"118642","DOI":"10.1016\/j.ijpharm.2019.118642","article-title":"Improvement strategies for the oral bioavailability of poorly water-soluble flavonoids: An overview","volume":"570","author":"Zhao","year":"2019","journal-title":"Int. J. Pharm."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Babii, C., Mihalache, G., Bahrin, L.G., Neagu, A.N., Gostin, I., Mihai, C.T., Sarbu, L.G., Birsa, L.M., and Stefan, M. (2018). A novel synthetic flavonoid with potent antibacterial properties: In Vitro activity and proposed mode of action. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0194898"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2200111","DOI":"10.1002\/macp.202200111","article-title":"Getting the terms right: Green, sustainable, or circular chemistry?","volume":"223","author":"Mutlu","year":"2022","journal-title":"Macromol. Chem. Phys."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Sheldon, R.A., Arends, I.W.C.E., and Hanefeld, U. (2007). Green Chemistry and Catalysis, Wiley.","DOI":"10.1002\/9783527611003"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/nj7543-379a","article-title":"Chemistry: Green refill","volume":"519","author":"Cernansky","year":"2015","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1038\/450810a","article-title":"Green chemistry","volume":"450","author":"Poliakoff","year":"2007","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Babii, C., Savu, M., Motrescu, I., Birsa, L.M., Sarbu, L.G., and Stefan, M. (2021). The antibacterial synthetic flavonoid BrCl-Flav exhibits important anti-Candida activity by damaging cell membrane integrity. Pharmaceuticals, 14.","DOI":"10.3390\/ph14111130"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2315","DOI":"10.1016\/j.bmcl.2014.03.071","article-title":"The antibacterial properties of sulfur containing flavonoids","volume":"24","author":"Bahrin","year":"2014","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Birsa, M.L., and Sarbu, L.G. (2022). An improved synthetic method for sensitive iodine containing tricyclic flavonoids. Molecules, 27.","DOI":"10.3390\/molecules27238430"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1007\/s11783-014-0681-x","article-title":"Catalytic wet air oxidation of phenol, nitrobenzene and aniline over the multi-walled carbon nanotubes (MWCNTs) as catalysts","volume":"9","author":"Yang","year":"2015","journal-title":"Front. Environ. Sci. Eng."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.molcata.2006.01.049","article-title":"One-pot synthesis of dihydropyrimidones using silica-supported heteropoly acid as an efficient and reusable catalyst: Improved protocol conditions for the Biginelli reaction","volume":"250","author":"Rafiee","year":"2006","journal-title":"J. Mol. Catal. A Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1080\/17518253.2010.523015","article-title":"Silica supported heteropolyacid catalyzed dehydration of aldoximes to nitriles and alcohols to alkenes","volume":"4","author":"Parghi","year":"2011","journal-title":"Green Chem. Lett. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9813","DOI":"10.1016\/S0040-4020(97)00628-5","article-title":"New flavones by a novel synthetic route","volume":"53","author":"Sandulache","year":"1997","journal-title":"Tetrahedron"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4529","DOI":"10.1128\/AAC.00624-09","article-title":"In vitro activities of panduratin A against clinical Staphylococcus strains","volume":"53","author":"Rukayadi","year":"2009","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Thebti, A., Meddeb, A., Ben Salem, I., Bakary, C., Ayari, S., Rezgui, F., Essafi-Benkhadir, K., Boudabous, A., and Ouzari, H.-I. (2023). Antimicrobial activities and mode of flavonoid actions. Antibiotics, 12.","DOI":"10.3390\/antibiotics12020225"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1007\/s11164-020-04359-6","article-title":"Synthesis and biological activity of new chalcone scaffolds as prospective antimicrobial agents","volume":"47","author":"Narwal","year":"2021","journal-title":"Res. Chem. Intermed."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"115834","DOI":"10.1016\/j.indcrop.2022.115834","article-title":"Prenylated flavonoids and derivatives isolated from the root barks of Sophora flavescens as potent antibacterial agents against Staphylococcus aureus","volume":"189","author":"Long","year":"2022","journal-title":"Ind. Crops Prod."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Xu, M., Wu, P., Shen, F., Ji, J., and Rakesh, K.P. (2019). Chalcone derivatives and their antibacterial activities: Current development. Bioorg. Chem., 91.","DOI":"10.1016\/j.bioorg.2019.103133"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5739","DOI":"10.1016\/j.ejmech.2010.09.031","article-title":"Synthesis of new chalcone derivatives containing a rhodanine-3-acetic acid moiety with potential anti-bacterial activity","volume":"45","author":"Chen","year":"2010","journal-title":"Eur. J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.1016\/j.bmc.2009.12.077","article-title":"Synthesis and biological screening of a combinatorial library of \u03b2-chlorovinyl chalcones as anticancer, anti-inflammatory and antimicrobial agents","volume":"18","author":"Bandgar","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7284","DOI":"10.3390\/molecules17067284","article-title":"Antibacterial, antifungal and cytotoxic activities of two flavonoids from Retama raetam flowers","volume":"17","author":"Edziri","year":"2012","journal-title":"Molecules"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Jin, Y.-S. (2019). Recent advances in natural antifungal flavonoids and their derivatives. Bioorg. Med. Chem. Lett., 29.","DOI":"10.1016\/j.bmcl.2019.07.048"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1038\/s41429-018-0048-9","article-title":"Design, synthesis, biological activity and structure-activity relationship studies of chalcone derivatives as potential anti-Candida agents","volume":"71","author":"Andrade","year":"2018","journal-title":"J. Antibiot."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1039\/C7MD00440K","article-title":"Synergistic antifungal effect of cyclized chalcone derivatives and fluconazole against Candida albicans","volume":"8","author":"Ahmad","year":"2017","journal-title":"Medchemcomm"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Kucerova-Chlupacova, M., Vyskovska-Tyllova, V., Richterova-Finkova, L., Kunes, J., Buchta, V., Vejsova, M., Paterova, P., Semelkova, L., Jandourek, O., and Opletalova, V. (2016). Novel halogenated pyrazine-based chalcones as potential antimicrobial drugs. Molecules, 21.","DOI":"10.3390\/molecules21111421"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.ejmech.2016.02.041","article-title":"Synthesis of newer 1,2,3-triazole linked chalcone and flavone hybrid compounds and evaluation of their antimicrobial and cytotoxic activities","volume":"113","author":"Kant","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_37","first-page":"57","article-title":"Mechanism of action and potential for use of tea catechin as an antiinfective agent","volume":"6","author":"Shimamura","year":"2007","journal-title":"Anti-Infect. Agents Med. Chem. (Former. Curr. Med. Chem. Anti-Infect. Agents)"}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/13\/9\/798\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:42:36Z","timestamp":1760110956000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/13\/9\/798"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,24]]},"references-count":37,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["antibiotics13090798"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics13090798","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,24]]}}}