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Current therapies, Pirfenidone and Nintedanib, slow disease progression but cannot reverse established fibrosis, underscoring the urgent need for innovative strategies. Oxidative stress and hypoxia\u2010inducible factor\u20101\u03b1 (HIF\u20101\u03b1) signaling are central to IPF pathogenesis, where the interplay between reactive oxygen species (ROS), TGF\u2010\u03b21, and stabilized HIF\u20101\u03b1 forms a self\u2010perpetuating loop that promotes fibroblast activation and extracellular matrix (ECM) deposition. To interrupt this pathological cycle, we rationally designed and synthesized four small molecules, two imidazole\u2010 and two pyrrole\u2010based derivatives, with dual antioxidants and HIF\u20101\u03b1 inhibitory potential. Their antioxidant potential was assessed using DPPH and DCFDA assays, while density functional theory (DFT) calculations and ADME profiling confirmed their chemical stability and drug\u2010likeness. In\u00a0vitro screening identified compound\n                    <jats:bold>2a<\/jats:bold>\n                    as the lead candidate based on its superior ability to inhibit HIF\u20101\u03b1 and suppress fibrotic markers, including collagen III, fibronectin, and vimentin, in TGF\u2010\u03b21\u2010stimulated A549 and MRC\u20105 cells. In\u00a0vivo,\n                    <jats:bold>2a<\/jats:bold>\n                    significantly attenuated collagen and fibronectin accumulation in a bleomycin\u2010induced pulmonary fibrosis model. Mechanistically, 2a inhibited phosphorylation of Smad3 and ERK, implicating modulation of both Smad and non\u2010Smad pathways in its anti\u2010fibrotic effects. These findings position compound\n                    <jats:bold>2a<\/jats:bold>\n                    as a promising dual\u2010targeted therapeutic candidate for IPF, capable of disrupting the ROS\u2013TGF\u2010\u03b21\u2013HIF\u20101\u03b1 axis and addressing key unmet clinical needs.\n                  <\/jats:p>","DOI":"10.1111\/cbdd.70163","type":"journal-article","created":{"date-parts":[[2025,8,16]],"date-time":"2025-08-16T08:54:33Z","timestamp":1755334473000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Synthesis, Anti\u2010Fibrotic Activity, and Density Functional Theory Calculations of Novel Carboxylic Acid Analogs Containing Pyrrole and Imidazole Rings"],"prefix":"10.1111","volume":"106","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-0758-2042","authenticated-orcid":false,"given":"Hiruni Nilshi Indeevarie","family":"Abeysiriwardhana","sequence":"first","affiliation":[{"name":"Interdisciplinary Graduate Program in Advanced Convergence Technology and Science Jeju National University  Jeju\u2010si Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin\u2010Hyuk","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine Jeju National University  Jeju\u2010si Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayusha","family":"Malla","sequence":"additional","affiliation":[{"name":"ACHEMBIO Inc  Jeju\u2010si Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoongho","family":"Lim","sequence":"additional","affiliation":[{"name":"Division of Bioscience and Biotechnology Konkuk University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chulhun","family":"Park","sequence":"additional","affiliation":[{"name":"College of Pharmacy Jeju National University  Jeju\u2010si Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang\u2010Soep","family":"Nahm","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine, College of Veterinary Medicine Konkuk University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4799-7584","authenticated-orcid":false,"given":"Moonjae","family":"Cho","sequence":"additional","affiliation":[{"name":"Interdisciplinary Graduate Program in Advanced Convergence Technology and Science Jeju National University  Jeju\u2010si Republic of Korea"},{"name":"Department of Biochemistry, School of Medicine Jeju National University  Jeju\u2010si Republic of Korea"},{"name":"ACHEMBIO Inc  Jeju\u2010si Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,16]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11233878"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.15420\/cfr.2021.30"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0283271"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/856918"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276\u2010024\u201001180\u20108"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2007.10.030"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00335.2010.\u2010Increasing"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2008.080382"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12890\u2010020\u20101142\u2010x"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2008.12.053"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.121.001031"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2012.11.021"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2009.09.018"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13765\u2010022\u201000764\u20100"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep42717"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00044\u2010023\u201003065\u20103"},{"key":"e_1_2_8_18_1","unstructured":"Flanders K. 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