{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T13:32:35Z","timestamp":1787837555883,"version":"build-2784847793"},"reference-count":47,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009392","name":"Prince Sattam bin Abdulaziz University","doi-asserted-by":"crossref","award":["PSAU\/2026\/R\/1447"],"award-info":[{"award-number":["PSAU\/2026\/R\/1447"]}],"id":[{"id":"10.13039\/100009392","id-type":"DOI","asserted-by":"crossref"}]},{"award":["PSAU\/2026\/R\/1447"],"award-info":[{"award-number":["PSAU\/2026\/R\/1447"]}],"id":[{"id":"https:\/\/ror.org\/04jt46d36","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Diabetes mellitus (DM) is a critical metabolic condition with escalated blood glucose levels caused by insulin resistance, restricted insulin production, and the activity of alpha-amylase and alpha-glucosidase enzymes. Methods: This current work focuses on the synthesis and evaluation of novel Pyrimidine-derived pyrazole-based thiadiazole derivatives to target DM by inhibiting \u03b1-amylase and \u03b1-glucosidase. Results: The findings exhibited that, except for three compounds, all other synthesized derivatives inhibited \u03b1-amylase and \u03b1-glucosidase enzymes with IC50 values ranging from 5.17 \u03bcM to 29.84 \u03bcM on \u03b1-amylase and 7.60 \u03bcM to 31.62 \u03bcM on \u03b1-glucosidase, in comparison to the standard drug Acarbose (\u03b1-amylase IC50 = 8.25 \u00b1 0.80 \u03bcM; \u03b1-glucosidase IC50 = 10.75 \u00b1 1.10 \u03bcM). Analogs 8g, 8k, and 8b displayed superior or comparable inhibitory activity compared to the reference drug Acarbose. The inhibition potential of the derivatives can be attributed to their stable contacts with crucial amino acid residues of targeted enzymes, as shown through molecular docking analysis. Moreover, DFT-calculated HOMO\u2013LUMO parameters and electrostatic potential (ESP) maps were used to gain complementary insight into the electronic characteristics, charge distribution, and potential interaction behavior of the synthesized derivatives, which supported the molecular docking observations. Conclusions: Experimental outcomes and in silico support display that these derivatives serve as potential leads for anti-diabetic drug development. These potent pyrimidine-derived pyrazole-based thiadiazole derivatives were comparable to an existing diabetic mellitus inhibitor, specifying potential for further therapeutic development and optimization against diabetic mellitus.<\/jats:p>","DOI":"10.3390\/ph19060915","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T06:57:17Z","timestamp":1781161037000},"page":"915","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Synthetic Elaboration, DFT Profiling, and Molecular-Dynamics-Guided Computational Validation Toward Anti-Diabetic Therapeutics: Tailored Pyrimidine-Derived Pyrazole-Thiadiazole Hybrid Scaffolds"],"prefix":"10.3390","volume":"19","author":[{"given":"Nahed Sail","family":"Alharthi","sequence":"first","affiliation":[{"name":"Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Alkharj 11942, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Jadon, A.S., Kaushik, M.P., Anitha, K., Bhatt, S., Bhadauriya, P., and Sharma, M. 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