{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:28:32Z","timestamp":1785403712460,"version":"3.56.0"},"reference-count":48,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Umm Al-Qura University, Saudi Arabia","award":["26UQU4290670GSSR01"],"award-info":[{"award-number":["26UQU4290670GSSR01"]}]},{"award":["26UQU4290670GSSR01"],"award-info":[{"award-number":["26UQU4290670GSSR01"]}],"id":[{"id":"https:\/\/ror.org\/01xjqrm90","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Backgroud: The growing prevalence of diabetes mellitus necessitates the development of safe and effective inhibitors of carbohydrate-metabolizing enzymes, particularly \u03b1-amylase and \u03b1-glucosidase. Methods: In this study, a series of pyrimidine\u2013oxadiazole derivatives (1\u201310) was synthesized and structurally characterized using elemental analysis, HREI-MS, and 1H\/13C NMR spectroscopy. The compounds were evaluated for in vitro inhibitory activity against both enzymes, with acarbose as the reference drug. Results: IC50 values ranged from 6.70 \u00b1 0.20 to 21.10 \u00b1 0.10 \u03bcM for \u03b1-amylase and 7.10 \u00b1 0.20 to 21.80 \u00b1 0.40 \u03bcM for \u03b1-glucosidase. Compounds 2, 3, and 6 displayed superior dual inhibitory activity compared to acarbose (IC50 = 10.10 \u00b1 0.20 and 10.50 \u00b1 0.10 \u03bcM, respectively). Structure\u2013activity relationship analysis revealed that electronic effects of aromatic substitutions significantly influenced enzyme inhibition. Molecular docking supported the experimental findings by demonstrating stable binding interactions within the enzyme active sites. Preliminary safety profiling in male Wistar rats showed no observable behavioral changes, hematological abnormalities, or hepatic and renal dysfunction following repeated administration of the lead compound. Conclusions: These results highlight pyrimidine\u2013oxadiazole derivatives as promising and well-tolerated dual enzyme inhibitors for further antidiabetic drug development.<\/jats:p>","DOI":"10.3390\/ph19071085","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T01:05:07Z","timestamp":1784163907000},"page":"1085","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Medicinally Tuned Pyrimidine\u2013Oxadiazole Hybrids: Synthetic Development, Enzyme-Targeted Evaluation, In Vivo Toxicological Assessment and Computational Investigations Against Diabetes Mellitus"],"prefix":"10.3390","volume":"19","author":[{"given":"Shifa","family":"Felemban","sequence":"first","affiliation":[{"name":"Department of Chemistry, Faculty of Applied Science, University College-Al Leith, University of Umm Al-Qura, Makkah 21955, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5294-2193","authenticated-orcid":false,"given":"M. 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