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This research focuses on discovering new chalcone derivatives with a stronger ability to stimulate AMPK in podocytes compared to 2\u2032\u2010hydroxychalcones <jats:bold>1<\/jats:bold>, <jats:bold>2<\/jats:bold>, and <jats:bold>3<\/jats:bold> reported from the earlier research. The results show that hydrogenated products (<jats:bold>4\u20136<\/jats:bold>) cannot exhibit considerably improved activity. Additionally, 2\u2032\u2010hydroxychalcone bearing 2,4,5\u2010triethoxy groups on the B\u2010ring (<jats:bold>10<\/jats:bold>) and 2,4,5\u2010trimethoxychalcones bearing 2\u2032,4\u2032\u2010, 2\u2032,5\u2032\u2010, or 2\u2032,6\u2032\u2010dimethoxy groups on the A\u2010ring (<jats:bold>17\u201319<\/jats:bold>) demonstrate potent AMPK activation with fold changes of 2.69, 2.36, 3.22, and 2.17, respectively, surpassing both the reference compound <jats:bold>1<\/jats:bold> (1.28) and metformin (1.88). The structure\u2013activity relationship shows that inserting dimethoxy groups on the A\u2010ring can strengthen the activity better than without inserting any group or inserting other moieties such as hydroxy, methylenedioxy, amino, trifluoromethyl, bromo, acetyl, 2,3\u2010dihydro\u20101,4\u2010dioxin ring, and benzene ring. Notably, 2,4,5\u2010trimethoxychalcone <jats:bold>23<\/jats:bold> possessing 2\u2032,4\u2032,5\u2032\u2010trimethoxy groups, <jats:italic>bis<\/jats:italic>\u2010chalcones <jats:bold>35<\/jats:bold> and <jats:bold>36<\/jats:bold>, and <jats:italic>tris<\/jats:italic>\u2010chalcone <jats:bold>37<\/jats:bold> is poorly soluble in the experiments. Compound <jats:bold>18<\/jats:bold> exhibits more potent activity than compounds <jats:bold>2<\/jats:bold> and <jats:bold>3<\/jats:bold> (2.48 and 2.73, respectively); therefore, it would be a promising candidate for further studies on AMPK\u2010stimulating activity.<\/jats:p>","DOI":"10.1002\/cmdc.202500177","type":"journal-article","created":{"date-parts":[[2025,5,24]],"date-time":"2025-05-24T10:29:07Z","timestamp":1748082547000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["AMPK Activation by 2\u2032\u2010Hydroxy\u20102,4,5\u2010Trimethoxychalcone Derivatives in Podocyte Cells"],"prefix":"10.1002","volume":"20","author":[{"given":"Vu\u2010Duy","family":"Nguyen","sequence":"first","affiliation":[{"name":"Faculty of Environment and Labour Safety Ton Duc Thang University  Ho Chi Minh City 700000 Vietnam"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chatchai","family":"Muanprasat","sequence":"additional","affiliation":[{"name":"Chakri Naruebodindra Medical Institute Faculty of Medicine Ramathibodi Hospital Mahidol University  Bang Phli Samut Prakarn 10540 Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suchada","family":"Kaewin","sequence":"additional","affiliation":[{"name":"Chakri Naruebodindra Medical Institute Faculty of Medicine Ramathibodi Hospital Mahidol University  Bang Phli Samut Prakarn 10540 Thailand"},{"name":"Department of Physiology Faculty of Science Mahidol University  Rama VI Road Rajathevi Bangkok 10400 Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wanangkan","family":"Poolsri","sequence":"additional","affiliation":[{"name":"Department of Science, Technology and Innovation Faculty of Science Chulabhorn Royal Academy  Bangkok 10210 Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5201-1324","authenticated-orcid":false,"given":"Warinthorn","family":"Chavasiri","sequence":"additional","affiliation":[{"name":"Center of Excellence in Natural Products Chemistry Department of Chemistry Faculty of Science Chulalongkorn University  Pathumwan Bangkok 10330 Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,6,11]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1080\/17460441.2018.1398731"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfu411"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2016.67"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2015.06.003"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00184.2016"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2005010055"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/emm.2016.81"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST20180625"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/boc.201800077"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2014.04.008"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2011010026"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2017.10.014"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph13120452"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2021.114687"},{"key":"e_1_2_8_16_1","first-page":"CD011919","volume":"1","author":"Jeyaraman M. 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