{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:56:14Z","timestamp":1785412574051,"version":"3.56.0"},"reference-count":40,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Scientific Research Fund of the Ministry of Higher Education","award":["MPH2192014"],"award-info":[{"award-number":["MPH2192014"]}]},{"DOI":"10.13039\/501100021772","name":"Deanship of Scientific Research at the University of Jordan","doi-asserted-by":"crossref","award":["2214"],"award-info":[{"award-number":["2214"]}],"id":[{"id":"10.13039\/501100021772","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100021772","name":"Deanship of Scientific Research at the University of Jordan","doi-asserted-by":"crossref","award":["2283"],"award-info":[{"award-number":["2283"]}],"id":[{"id":"10.13039\/501100021772","id-type":"DOI","asserted-by":"crossref"}]},{"award":["2214"],"award-info":[{"award-number":["2214"]}],"id":[{"id":"https:\/\/ror.org\/05k89ew48","id-type":"ROR","asserted-by":"publisher"}]},{"award":["2283"],"award-info":[{"award-number":["2283"]}],"id":[{"id":"https:\/\/ror.org\/05k89ew48","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Daniel Turnberg Travel Fellowship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Chronic oxidative stress and lipid imbalance drive metabolic disorders such as obesity and non-alcoholic fatty liver disease, yet few therapies target the upstream redox imbalance in key tissues. Human carbonic anhydrase III (hCA III), a redox-associated enzyme enriched in liver and adipose tissue, has long remained pharmacologically elusive due to its low catalytic activity and lack of modulators. Here, we identify fragment-like nicotinic acid derivatives as non-sulfonamide hCA III modulators and evaluate their associated cellular effects. Using an esterase activity assay, we screened 25 analogues and identified two fragment-like hits, compound 17 (2-thioethyl) and compound 22 (6-morpholino), with IC50 values of 487 and 361 \u00b5M, respectively. Orthogonal thermal shift analysis supported compound-protein interaction, and selected hits were subsequently evaluated in HepG2 cells. Both compounds were associated with reduced CA3 mRNA expression after treatment at 1 \u00b5M, while their cellular phenotypes diverged, with compound 22 increasing ROS under oxidative stress conditions and compound 17 affecting mitochondrial membrane potential. Taken together, these findings identify tractable nicotinic acid-derived fragment hits and associated cellular phenotypes that warrant further mechanistic investigation. These fragment-like hits provide a practical starting point for studying the redox-linked biology of hCA III.<\/jats:p>","DOI":"10.3390\/biom16040599","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T16:30:36Z","timestamp":1776443436000},"page":"599","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fragment-Derived Nicotinic Acid Analogues Inhibit hCA III and Downregulate CA3 Expression in HepG2 Cells"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4978-5059","authenticated-orcid":false,"given":"Areej","family":"Abuhammad","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Sabri","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nidaa A.","family":"Ababneh","sequence":"additional","affiliation":[{"name":"Cell Therapy Center, The University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rya A.","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5039-8764","authenticated-orcid":false,"given":"Mohammad A.","family":"Ismail","sequence":"additional","affiliation":[{"name":"Cell Therapy Center, The University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adan","family":"Madadha","sequence":"additional","affiliation":[{"name":"Cell Therapy Center, The University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dareen T.","family":"Yazjeen","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rama J.","family":"Alghanem","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali M.","family":"Qaisi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuf","family":"Al-Hiari","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kapil","family":"Gupta","sequence":"additional","affiliation":[{"name":"School of Biochemistry, University of Bristol, Bristol BS8 1TD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7518-9045","authenticated-orcid":false,"given":"Imre","family":"Berger","sequence":"additional","affiliation":[{"name":"School of Biochemistry, University of Bristol, Bristol BS8 1TD, UK"},{"name":"Bristol Synthetic Biology Centre BrisSynBio, Bristol BS8 1TD, UK"},{"name":"Max Planck Bristol Centre for Minimal Biology, Bristol BS8 1TS, UK"},{"name":"School of Chemistry, University of Bristol, Bristol BS8 1TS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edith","family":"Sim","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"ref_1","unstructured":"WHO (2025, May 16). 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