{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T15:58:14Z","timestamp":1765814294572,"version":"3.48.0"},"reference-count":38,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,14]],"date-time":"2025-12-14T00:00:00Z","timestamp":1765670400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Russian Scientific Foundation","award":["24-25-00120"],"award-info":[{"award-number":["24-25-00120"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Metabolic syndrome, a collective term for lipid and carbohydrate disorders in the organism, is the primary cause of type 2 diabetes mellitus development and its associated systemic side effects. The current approach for the medical treatment of this condition usually requires multiple medications, targeting multiple pathophysiological pathways. A promising drug class in that regard is the dual PPAR\u03b1\/\u03b3 agonists, which impact both lipid and carbohydrate metabolism, yet to this day the vast majority of them have not passed the clinical trials, due to potential toxicity risks. In the present study we synthesized and tested a series of monoterpene-substituted (S)-2-ethoxy-3-(4-(4-hydroxyphenethoxy)phenyl)propanoic acids as potentially effective and safe novel dual PPAR\u03b1\/\u03b3 agonists. In vitro studies showed that nearly all of the tested compounds were sufficiently active towards both PPAR\u03b1 and PPAR\u03b3. All compounds were tested in vivo, using C57BL\/6 Ay\/a mice with T2DM symptoms, in order to evaluate their impact on carbohydrate and lipid metabolism. The most promising of them was found to be compound 5h, containing a cumin fragment, which showed pronounced hypoglycemic activity by boosting tissue insulin sensitivity and hypolipidemic effects manifested by reductions in fat tissue mass and blood triglyceride levels, while simultaneously displaying a relatively safe profile.<\/jats:p>","DOI":"10.3390\/molecules30244775","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T15:52:59Z","timestamp":1765813979000},"page":"4775","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design and Biological Evaluation of Monoterpene-Conjugated (S)-2-Ethoxy-3-(4-(4-hydroxyphenethoxy)phenyl)propanoic Acids as New Dual PPAR\u03b1\/\u03b3 Agonists"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6415-5840","authenticated-orcid":false,"given":"Sergey A.","family":"Borisov","sequence":"first","affiliation":[{"name":"N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Akademika Lavrentieva Ave. 9, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0532-0815","authenticated-orcid":false,"given":"Mikhail E.","family":"Blokhin","sequence":"additional","affiliation":[{"name":"N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Akademika Lavrentieva Ave. 9, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yulia V.","family":"Meshkova","sequence":"additional","affiliation":[{"name":"N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Akademika Lavrentieva Ave. 9, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9500-1713","authenticated-orcid":false,"given":"Maria K.","family":"Marenina","sequence":"additional","affiliation":[{"name":"N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Akademika Lavrentieva Ave. 9, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8496-0230","authenticated-orcid":false,"given":"Nataliya A.","family":"Zhukova","sequence":"additional","affiliation":[{"name":"N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Akademika Lavrentieva Ave. 9, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1095-3692","authenticated-orcid":false,"given":"Sophia V.","family":"Pavlova","sequence":"additional","affiliation":[{"name":"Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Akademika Lavrentieva Ave. 10, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9170-6214","authenticated-orcid":false,"given":"Anastasiya V.","family":"Lastovka","sequence":"additional","affiliation":[{"name":"N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Akademika Lavrentieva Ave. 9, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1827-3309","authenticated-orcid":false,"given":"Vladislav V.","family":"Fomenko","sequence":"additional","affiliation":[{"name":"N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Akademika Lavrentieva Ave. 9, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor P.","family":"Zhurakovsky","sequence":"additional","affiliation":[{"name":"Department of Pathological Physiology and Clinical Pathophysiology, Faculty of Medicine, Novosibirsk State Medical University, Krasny Pr-t. 52, 630091 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8627-3453","authenticated-orcid":false,"given":"Olga A.","family":"Luzina","sequence":"additional","affiliation":[{"name":"N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Akademika Lavrentieva Ave. 9, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5906-4223","authenticated-orcid":false,"given":"Mikhail V.","family":"Khvostov","sequence":"additional","affiliation":[{"name":"N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Akademika Lavrentieva Ave. 9, 630090 Novosibirsk, Russia"},{"name":"V. Zelman Faculty for the Medicine and Psychology, Novosibirsk State University, Pirogova Str. 1, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1878-4467","authenticated-orcid":false,"given":"Dmitry A.","family":"Kudlay","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy, I. M. Sechenov First Moscow State Medical University, St. Trubetskaya 8\/2, 119991 Moscow, Russia"},{"name":"Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Leninskie Gory 1\/73, 119234 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nariman F.","family":"Salakhutdinov","sequence":"additional","affiliation":[{"name":"N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Akademika Lavrentieva Ave. 9, 630090 Novosibirsk, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/s41572-024-00563-5","article-title":"Metabolic syndrome","volume":"10","author":"Neeland","year":"2024","journal-title":"Nat. Rev. Dis. 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