{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T16:02:13Z","timestamp":1772985733970,"version":"3.50.1"},"reference-count":24,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T00:00:00Z","timestamp":1770508800000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Niflumic acid is a potent NSAID, while its long\u2010term therapy can cause gastrointestinal complications. This study explores the prodrug approach of niflumic acid with natural antioxidant ethyl ferulate to improve its pharmacokinetics, thereby reducing gastrointestinal side effects. The primary objective was to develop niflumic acid prodrug with reduced gastric irritation, establish synthetic methods, characterize the prodrug, and evaluate their pharmacological activities. The prodrug was synthesized using the Steglich esterification method and characterized by IR, NMR, mass spectrometry, and elemental analysis. Further, in vitro hydrolysis, partition coefficient determination, protein binding studies, and in silico ADMET prediction were carried out. The pharmacological evaluation encompassed in vitro cytotoxicity assessments, anti\u2010arthritic investigations, and in vivo studies on anti\u2010inflammatory and ulcerogenic effects. The hydrolysis of the prodrug resulted in the release of niflumic acid in both simulated gastric fluid and simulated intestinal fluid, adhering to first\u2010order kinetics, with a half\u2010life of 230.4\u2009min. Results showed that the prodrug exhibited higher lipophilicity, reduced gastric discomfort, and improved anti\u2010inflammatory, cytotoxic, and anti\u2010arthritic activities compared with niflumic acid. The bioconjugation of niflumic acid with ethyl ferulate significantly reduced gastrointestinal side effects while maintaining or enhancing therapeutic efficacy. The findings indicate that the synthesized prodrug represents a promising candidate for the advancement of safer and more effective anti\u2010inflammatory therapies.<\/jats:p>","DOI":"10.1002\/ardp.70200","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T04:56:10Z","timestamp":1770612970000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Harnessing Hybrid Chemistry: Novel Ethyl Ferulate Ester of Niflumic Acid for Enhanced Therapeutic Benefits"],"prefix":"10.1002","volume":"359","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4097-2540","authenticated-orcid":false,"given":"Rahila P.","family":"Chavilkad","sequence":"first","affiliation":[{"name":"Center for Experimental Drug Design and Development, Department of Pharmaceutical Chemistry Al Shifa College of Pharmacy Perinthalmanna Kerala India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7058-2590","authenticated-orcid":false,"given":"Ramsiya","family":"Kottassery","sequence":"additional","affiliation":[{"name":"Center for Experimental Drug Design and Development, Department of Pharmaceutical Chemistry Al Shifa College of Pharmacy Perinthalmanna Kerala India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0772-7865","authenticated-orcid":false,"given":"Shafnaz A.","family":"Rahman","sequence":"additional","affiliation":[{"name":"Center for Experimental Drug Design and Development, Department of Pharmaceutical Chemistry Al Shifa College of Pharmacy Perinthalmanna Kerala India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7882-8412","authenticated-orcid":false,"given":"Shebina P.","family":"Rasheed","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Analysis Al Shifa College of Pharmacy Perinthalmanna Kerala India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9564-2158","authenticated-orcid":false,"given":"Pattilthodika","family":"Suhail","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Al Shifa College of Pharmacy Perinthalmanna Kerala India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arun","family":"Rasheed","sequence":"additional","affiliation":[{"name":"Center for Experimental Drug Design and Development, Department of Pharmaceutical Chemistry Al Shifa College of Pharmacy Perinthalmanna Kerala India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,2,8]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2017.05.009"},{"key":"e_1_2_9_3_1","unstructured":"GIB M.National Library of Medicine (US). National Center for Biotechnology Information.2004 https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Niflumic-acid."},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-012656975-9\/50018-3"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm101085j"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1080\/13543776.2019.1568410"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2011.10.015"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1254\/jphs.09146FP"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.197805221"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00044-011-9866-z"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.2478\/v10007-010-0003-1"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.31351\/vol30iss1pp240-248"},{"issue":"552","key":"e_1_2_9_13_1","first-page":"1","article-title":"Galactosylated Prodrugs: A Strategy to Improve the Profile of Nonsteroidal Anti\u2010Inflammatory Drugs","volume":"15","author":"Sodano F.","year":"2022","journal-title":"Pharmaceuticals"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/qsar.200730051"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.33263\/LIANBS134.167"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-080-5_20"},{"issue":"4","key":"e_1_2_9_17_1","first-page":"095","article-title":"Valuation of Anticancer Activity of Annona Muricata Leaf Targeting FGFR3 and EGFR Receptors Against Bladder and Lung Cancer","volume":"15","author":"Suhail P.","year":"2025","journal-title":"Journal of Applied Pharmaceutical Science"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.25083\/rbl\/25.4\/1832.1842"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.5115\/acb.19.009"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.plipres.2007.01.001"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2010.02.007"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.4103\/0253-7613.161270"},{"key":"e_1_2_9_23_1","first-page":"28","article-title":"In Vitro Protein Denatur Ation Inhibition Assay of Eucalyptus Globulus and Glycine max for Potential Anti\u2010Inflammatory Activity","volume":"8","author":"Mirke N. 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