{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T22:36:51Z","timestamp":1793227011783,"version":"4.5.0"},"reference-count":34,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T00:00:00Z","timestamp":1726790400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Due to the serious gastrointestinal side effects associated with prolonged use of current anti\u2010inflammatory therapies, various strategies such as the regulation of nitric oxide (NO) and prostaglandin E<jats:sub>2<\/jats:sub> (PGE<jats:sub>2<\/jats:sub>) production have been explored in the field of anti\u2010inflammatory drug development. In this study, a series of disubstituted 1,3,4\u2010oxadiazoles (<jats:bold>3a\u2013f<\/jats:bold> and <jats:bold>4a\u2013f<\/jats:bold>) and their cyclized 1,2,4\u2010triazole derivatives (<jats:bold>5a\u2013e<\/jats:bold> and <jats:bold>6a\u2013e<\/jats:bold>) were synthesized and tested for their NO, PGE<jats:sub>2<\/jats:sub>, and interleukin\u20106 (IL\u20106) releasing inhibition ability. All of the compounds were observed to reduce lipopolysaccharide (LPS)\u2010induced nitrite production in a concentration\u2010dependent manner. Moreover, compounds <jats:bold>3b<\/jats:bold> (50\u2009\u03bcM) and <jats:bold>6d<\/jats:bold> (1\u2009\u03bcM) exhibited 63% and 49% inhibition, respectively, while indomethacin showed 52% at 100\u2009\u03bcM. Based on a preliminary NO inhibition assay, 10 of the compounds (<jats:bold>3a<\/jats:bold>, <jats:bold>3b<\/jats:bold>, <jats:bold>3e<\/jats:bold>, <jats:bold>4b<\/jats:bold>, <jats:bold>4d<\/jats:bold>, <jats:bold>6a\u2013e<\/jats:bold>) were selected to be evaluated for in vitro PGE<jats:sub>2<\/jats:sub>, IL\u20106, and inducible nitric oxide synthase (iNOS) inhibition. Notably, compound <jats:bold>6d<\/jats:bold> proved to be the most active of the series with the lowest dose (1\u2009\u00b5M), in comparison to the other further tested compounds (5\u2013100\u2009\u00b5M) and the reference drug indomethacin (100\u2009\u00b5M). The inhibitory activity of the compounds was supported by docking simulations into the binding site of the iNOS protein receptor (Protein Data Bank [PDB]ID: 3E7G). The data showing that <jats:bold>4d<\/jats:bold> reduced iNOS levels the most can be explained by the H\u2010bond with Tyr347 through oxadiazole and \u03c0\u2013halogen interactions through the <jats:italic>p<\/jats:italic>\u2010bromo, in addition to aromatic interactions with protoporphyrin IX.<\/jats:p>","DOI":"10.1002\/ardp.202400238","type":"journal-article","created":{"date-parts":[[2024,9,21]],"date-time":"2024-09-21T06:14:57Z","timestamp":1726899297000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["iNOS\/PGE<sub>2<\/sub> inhibitors as a novel template for analgesic\/anti\u2010inflammatory activity: Design, synthesis, in vitro biological activity and docking studies"],"prefix":"10.1002","volume":"357","author":[{"given":"Ayca","family":"Erdogan","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry Faculty of Pharmacy, Yeditepe University Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yagmur","family":"Ozhan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Toxicology Faculty of Pharmacy, Yeditepe University Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hande","family":"Sipahi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Toxicology Faculty of Pharmacy, Yeditepe University Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enise Ece","family":"Gurdal","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry Faculty of Chemistry, Martin Luther University Halle\u2010Wittenberg Halle (Saale) Germany"},{"name":"Department of Nano\u2010Optics Max Planck Institute for the Science of Light Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5985-9261","authenticated-orcid":false,"given":"Wolfgang","family":"Sippl","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Institute of Pharmacy, Martin Luther University Halle\u2010Wittenberg Halle (Saale) Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7662-9364","authenticated-orcid":false,"given":"Meric","family":"Koksal","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry Faculty of Pharmacy, Yeditepe University Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,9,20]]},"reference":[{"key":"e_1_2_8_2_1","volume-title":"Foye's Principles of Medicinal Chemistry","author":"Lemke T. L.","year":"2013"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.01.022"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.23208"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.BIOORG.2023.106716"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20092322"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1733"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jff.2015.03.009"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2018.04.004"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)42133-3"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2019.126884"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2020.104439"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ardp.202000061"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2023.115496"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2013.12.018"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2019.103376"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2008.09.005"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2007.11.014"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.2174\/138955712801264800"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0031-1296550"},{"key":"e_1_2_8_21_1","unstructured":"S. M.Edward Merck Co. USA PCT Int. Appl. WO 2004 45 508 (Cl. A61k) 3 Jun 2004 US Appl. PV426 529 40 pp; CA2002 141 23432m."},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b00608"},{"key":"e_1_2_8_23_1","first-page":"1069","volume":"62","author":"Koksal M.","year":"2011","journal-title":"Rev. Chim."},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2020.113408"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules25112695"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sajb.2021.01.028"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/med.21636"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm051256o"},{"key":"e_1_2_8_29_1","unstructured":"Schr\u00f6dinger Release2019\u20104:Glide Schr\u00f6dinger LLC. New York NY2019."},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444902003451"},{"key":"e_1_2_8_31_1","unstructured":"Schr\u00f6dinger Release 2019\u20104:Protein Preparation Wizard; Epik Schr\u00f6dinger LLC New York NY 2019;Impact Schr\u00f6dinger LLC New York NY;Prime Schr\u00f6dinger LLC NewYork NY 2019."},{"key":"e_1_2_8_32_1","unstructured":"Schr\u00f6dinger Release 2019\u20104:Maestro Schr\u00f6dinger LLC New York NY 2019."},{"key":"e_1_2_8_33_1","unstructured":"Schr\u00f6dinger Release 2019\u20104:LigPrep Schr\u00f6dinger LLC New York NY 2019."},{"key":"e_1_2_8_34_1","unstructured":"Schr\u00f6dinger Release 2019\u20104:ConfGen Schr\u00f6dinger LLC New York NY 2019."},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/ci100015j"}],"container-title":["Archiv der Pharmazie"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ardp.202400238","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T10:09:40Z","timestamp":1733134180000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ardp.202400238"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,20]]},"references-count":34,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2024,12]]}},"alternative-id":["10.1002\/ardp.202400238"],"URL":"https:\/\/doi.org\/10.1002\/ardp.202400238","archive":["Portico"],"relation":{},"ISSN":["0365-6233","1521-4184"],"issn-type":[{"value":"0365-6233","type":"print"},{"value":"1521-4184","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,20]]},"assertion":[{"value":"2024-04-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-29","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"2400238"}}