{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T08:58:30Z","timestamp":1761555510977,"version":"build-2065373602"},"reference-count":61,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T00:00:00Z","timestamp":1761264000000},"content-version":"vor","delay-in-days":23,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    \u2010associated infections pose a significant clinical challenge due to biofilm formation, which contributes to antibiotic resistance and persistent infections. The prevalence of methicillin\u2010resistant\n                    <jats:italic>S. aureus<\/jats:italic>\n                    (MRSA) further exacerbates this issue, underscoring the urgent need for effective therapeutic strategies. In this study, we report a potent and selective second\u2010generation MRSA biofilm inhibitor (\n                    <jats:bold>4ad<\/jats:bold>\n                    ), which showed a minimum biofilm inhibition concentration (MBIC\n                    <jats:sub>50<\/jats:sub>\n                    ) of 0.78\u2009\u00b5g\/mL and demonstrated \u2265\u2009128\u2010fold selectivity for biofilm inhibition over planktonic growth. Through structural optimisation and fragmentation, we further identified a truncated analogue (\n                    <jats:bold>5a<\/jats:bold>\n                    ) that effectively eradicated a preformed MRSA biofilm, with a minimum biofilm eradication concentration (MBEC\n                    <jats:sub>50<\/jats:sub>\n                    ) of 0.78\u2009\u00b5g\/mL\u2014outperforming both the first\u2010generation hit (\n                    <jats:bold>4e<\/jats:bold>\n                    ) and the clinically used antibiotics oxacillin and vancomycin. Notably, both\n                    <jats:bold>4ad<\/jats:bold>\n                    and\n                    <jats:bold>5a<\/jats:bold>\n                    exhibited no significant impact on planktonic bacterial viability or Vero cell cytotoxicity. Given the broad\u2010spectrum antibiofilm activity of\n                    <jats:bold>4e<\/jats:bold>\n                    against\n                    <jats:italic>S. aureus<\/jats:italic>\n                    , we investigated its combinatorial effects with antibiotics.\n                    <jats:bold>4e<\/jats:bold>\n                    demonstrated additive effects in combination with vancomycin, erythromycin, and amoxicillin. Importantly, both structure\u2013activity relationship (SAR) and quantitative structure\u2013activity relationship (QSAR) analyses identified key structural features associated with antibiofilm activity. Collectively, these findings support further development of pyrazolyl indolenine derivatives and mechanistic studies aimed at combating antibiotic\u2010resistant\n                    <jats:italic>S. aureus<\/jats:italic>\n                    biofilm.\n                  <\/jats:p>","DOI":"10.1002\/ardp.70126","type":"journal-article","created":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T07:32:23Z","timestamp":1761291143000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Discovery and Structure\u2010Activity Relationship Study of Pyrazolyl Indolenine Derivatives as\n                    <i>Staphylococcus aureus<\/i>\n                    Biofilm Inhibitors"],"prefix":"10.1002","volume":"358","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-0261-1662","authenticated-orcid":false,"given":"Jason Jonah","family":"James","sequence":"first","affiliation":[{"name":"Nanotechnology and Catalysis Research Centre, Institute for Advanced Studies Universiti Malaya  Kuala Lumpur Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng Hong","family":"Yap","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Faculty of Medicine Universiti Malaya  Kuala Lumpur Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2369-6787","authenticated-orcid":false,"given":"Neni","family":"Frimayanti","sequence":"additional","affiliation":[{"name":"Sekolah Tinggi Ilmu Farmasi Riau  Pekanbaru Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nurshamimi Nor","family":"Rashid","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Faculty of Medicine Universiti Malaya  Kuala Lumpur Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sun Tee","family":"Tay","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Faculty of Medicine Universiti Malaya  Kuala Lumpur Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5650-9119","authenticated-orcid":false,"given":"Chin Fei","family":"Chee","sequence":"additional","affiliation":[{"name":"Nanotechnology and Catalysis Research Centre, Institute for Advanced Studies Universiti Malaya  Kuala Lumpur Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,10,24]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)02185-7"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30925-9"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.genrep.2020.100739"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00134-14"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/femsre\/fux010"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00198-12"},{"key":"e_1_2_10_8_1","first-page":"175","article-title":"Comparison of Biofilm Formation Between Methicillin\u2010Resistant and Methicillin\u2010Susceptible Isolates of Staphylococcus aureus","volume":"20","author":"Ghasemian A.","year":"2016","journal-title":"Iranian Biomedical Journal"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1177\/0036850419898659"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2018.08.021"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2014.00178"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/toxins8070198"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00819-13"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/bmb\/ldx046"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1159\/000501788"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-0691.2012.03914.x"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.18683\/germs.2022.1328"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/toxins8030072"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2009.12.011"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.00155-21"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.0c00662"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.1c00030"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2022.103731"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2021.119306"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1504022112"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1904700116"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abd6737"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2019.02.007"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2020.112892"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2017.06.043"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2016.07.030"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2023.117485"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arabjc.2021.103670"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.3109\/13880209.2010.519390"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm4004285"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph13090210"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.872943"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2019.02.007"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1039\/C4RA08728C"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2014.09.009"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.02320-21"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.02280-06"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2015.00001"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6968.2007.00688.x"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13568-016-0297-6"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2011.02.014"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12790"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1086\/317606"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00253-012-4674-z"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00877-12"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1080\/21505594.2017.1313372"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.2c00206"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.1c00402"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00766-08"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/1615-9861(200206)2:6<747::AID-PROT747>3.0.CO;2-V"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00871-09"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0463.2007.apm_630.x"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2024.106886"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1089\/mdr.2020.0178"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep42717"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms12128626"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1020869118689"}],"container-title":["Archiv der Pharmazie"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ardp.70126","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T08:53:13Z","timestamp":1761555193000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ardp.70126"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10]]},"references-count":61,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1002\/ardp.70126"],"URL":"https:\/\/doi.org\/10.1002\/ardp.70126","archive":["Portico"],"relation":{},"ISSN":["0365-6233","1521-4184"],"issn-type":[{"type":"print","value":"0365-6233"},{"type":"electronic","value":"1521-4184"}],"subject":[],"published":{"date-parts":[[2025,10]]},"assertion":[{"value":"2025-05-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-24","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70126"}}