{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T06:50:23Z","timestamp":1756191023377,"version":"3.41.2"},"reference-count":45,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2024,7,4]],"date-time":"2024-07-04T00:00:00Z","timestamp":1720051200000},"content-version":"vor","delay-in-days":0,"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":[[2024,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In our previous study, we reported a series of <jats:italic>N<\/jats:italic>\u2010(9,10\u2010anthraquinone\u20102\u2010carbonyl) amino acid derivatives as novel inhibitors of xanthine oxidase (XO). Recognizing the suboptimal drug\u2010like properties associated with the anthraquinone moiety, we embarked on a nonanthraquinone medicinal chemistry exploration in the current investigation. Through systematic structure\u2013activity relationship (SAR) studies, we identified a series of 4\u2010(isopentyloxy)\u20103\u2010nitrobenzamide derivatives exhibiting excellent in vitro potency against XO. The optimized compound, 4\u2010isopentyloxy\u2010<jats:italic>N<\/jats:italic>\u2010(1<jats:italic>H<\/jats:italic>\u2010pyrazol\u20103\u2010yl)\u20103\u2010nitrobenzamide (<jats:bold>6k<\/jats:bold>), demonstrated exceptional in vitro potency with an IC<jats:sub>50<\/jats:sub> value of 0.13\u2009\u03bcM. Compound <jats:bold>6k<\/jats:bold> showed favorable drug\u2010like characteristics with ligand efficiency (LE) and lipophilic ligand efficiency (LLE) values of 0.41 and 3.73, respectively. In comparison to the initial compound <jats:bold>1d<\/jats:bold>, <jats:bold>6k<\/jats:bold> exhibited a substantial 24\u2010fold improvement in IC<jats:sub>50<\/jats:sub>, along with a 1.6\u2010fold enhancement in LE and a 3.7\u2010fold increase in LLE. Molecular modeling studies provided insights into the strong interactions of <jats:bold>6k<\/jats:bold> with critical amino acid residues within the active site. Furthermore, in vivo hypouricemic investigations convincingly demonstrated that <jats:bold>6k<\/jats:bold> significantly reduced serum uric acid levels in rats. The MTT results revealed that compound <jats:bold>6k<\/jats:bold> is nontoxic to healthy cells. The gastric and intestinal stability assay demonstrated that compound <jats:bold>6k<\/jats:bold> exhibits good stability in the gastric and intestinal environments. In conclusion, compound <jats:bold>6k<\/jats:bold> emerges as a promising lead compound, showcasing both exceptional in vitro potency and favorable drug\u2010like characteristics, thereby warranting further exploration.<\/jats:p>","DOI":"10.1002\/ardp.202400137","type":"journal-article","created":{"date-parts":[[2024,7,4]],"date-time":"2024-07-04T13:46:03Z","timestamp":1720100763000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Discovery of 4\u2010(isopentyloxy)\u20103\u2010nitrobenzamide derivatives as xanthine oxidase inhibitors through a non\u2010anthraquinone exploration"],"prefix":"10.1002","volume":"357","author":[{"given":"Shuai","family":"Guo","sequence":"first","affiliation":[{"name":"School of Pharmacy\/Key Laboratory of Research and Development of Small Molecule Targeted Antitumor Drugs China Medical University Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Pharmacy\/Key Laboratory of Research and Development of Small Molecule Targeted Antitumor Drugs China Medical University Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmacy\/Key Laboratory of Research and Development of Small Molecule Targeted Antitumor Drugs China Medical University Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Song\u2010ye","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmacy\/Key Laboratory of Research and Development of Small Molecule Targeted Antitumor Drugs China Medical University Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong\u2010ye","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Pharmacy\/Key Laboratory of Research and Development of Small Molecule Targeted Antitumor Drugs China Medical University Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gong\u2010hui","family":"Ge","sequence":"additional","affiliation":[{"name":"School of Pharmacy\/Key Laboratory of Research and Development of Small Molecule Targeted Antitumor Drugs China Medical University Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy\/Key Laboratory of Research and Development of Small Molecule Targeted Antitumor Drugs China Medical University Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xing\u2010yang","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Pharmacy\/Key Laboratory of Research and Development of Small Molecule Targeted Antitumor Drugs China Medical University Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ben","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Pharmacy\/Key Laboratory of Research and Development of Small Molecule Targeted Antitumor Drugs China Medical University Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting\u2010ting","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmacy\/Key Laboratory of Research and Development of Small Molecule Targeted Antitumor Drugs China Medical University Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xian\u2010feng","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Pharmacy\/Key Laboratory of Research and Development of Small Molecule Targeted Antitumor Drugs China Medical University Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan\u2010ping","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy\/Key Laboratory of Research and Development of Small Molecule Targeted Antitumor Drugs China Medical University Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fan\u2010hao","family":"Meng","sequence":"additional","affiliation":[{"name":"School of Pharmacy\/Key Laboratory of Research and Development of Small Molecule Targeted Antitumor Drugs China Medical University Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9001-7364","authenticated-orcid":false,"given":"Ting\u2010jian","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmacy\/Key Laboratory of Research and Development of Small Molecule Targeted Antitumor Drugs China Medical University Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,7,4]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.791983"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2015.91"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/eci.13937"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1177\/20420188241227295"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(23)00232-1"},{"key":"e_1_2_8_7_1","unstructured":"GBD 2021 Diseases and Injuries Collaborators Lancet. 2024 403 2133."},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2016-209707"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.41247"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-019-0115-y"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1080\/13543776.2020.1811233"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201900034"},{"key":"e_1_2_8_13_1","volume":"2014","author":"Seth R.","year":"2014","journal-title":"Cochrane Database Syst. Rev."},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2008.02.021"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.58.1.6"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcpt.12392"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.b17-00284"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2021.113928"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1710895"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)32234-0"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2021.104654"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2015.08.056"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2018.01.096"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2016.08.019"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2021.116117"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2020.112077"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2017.03.002"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2017.11.071"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2017.04.048"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/cbdd.13156"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2022.128582"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1021\/bc200389w"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1248\/cpb.c20-00206"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm901137j"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jnatprod.5b00947"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4163"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202008528"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.4c02116"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2021.105417"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2019.111717"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2017.09.051"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2023.106403"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2021.109536"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0400973101"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2016.03.007"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/0010-4655(95)00042-E"}],"container-title":["Archiv der Pharmazie"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ardp.202400137","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,14]],"date-time":"2025-01-14T06:21:50Z","timestamp":1736835710000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ardp.202400137"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,4]]},"references-count":45,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2024,10]]}},"alternative-id":["10.1002\/ardp.202400137"],"URL":"https:\/\/doi.org\/10.1002\/ardp.202400137","archive":["Portico"],"relation":{},"ISSN":["0365-6233","1521-4184"],"issn-type":[{"type":"print","value":"0365-6233"},{"type":"electronic","value":"1521-4184"}],"subject":[],"published":{"date-parts":[[2024,7,4]]},"assertion":[{"value":"2024-02-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-13","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2400137"}}