{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T21:33:18Z","timestamp":1769981598141,"version":"3.49.0"},"reference-count":77,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T00:00:00Z","timestamp":1750896000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: The need for dual-targeted enzyme inhibitors is critical in addressing complex diseases like Alzheimer\u2019s and glaucoma. Imidazothiadiazole and chalcone moieties are known for diverse bioactivities. This study aimed to develop novel imidazothiadiazole\u2013chalcone hybrids as potential inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase isoforms (hCAs), specifically hCA I and hCA II. Methods: Four hybrid molecules (8a\u20138d) were synthesized and structurally confirmed via 1H NMR, 13C NMR, FT-IR, MS, and elemental analysis techniques. Their enzyme inhibitory activities were assessed using Ellman\u2019s and Verpoorte\u2019s methods. Molecular docking and 100 ns molecular dynamics (MD) simulations were conducted to examine binding interactions. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were predicted using the pkCSM platform. Results: All compounds showed strong enzyme inhibition: AChE (Ki: 3.86\u201311.35 nM), BChE (Ki: 1.01\u20131.78 nM), hCA I (Ki: 45.13\u201381.24 nM), and hCA II (Ki: 36.08\u201352.45 nM). Docking analyses confirmed favorable binding, particularly with active-site residues. MD simulations demonstrated stable interactions throughout 100 ns. Compound 8a exhibited the highest cholinesterase inhibition, while compounds 8d and 8c were the most potent against hCA I and hCA II, respectively. The ADMET results showed high absorption and acceptable safety, with mild mutagenicity or cardiotoxicity concerns in select compounds. Conclusions: These findings suggest that imidazothiadiazole\u2013chalcone hybrids are promising multi-target enzyme inhibitors. Their potent activity, structural stability, and pharmacokinetic potential support their further development for therapeutic use in neurodegenerative and ocular diseases.<\/jats:p>","DOI":"10.3390\/ph18070962","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T07:55:43Z","timestamp":1751442943000},"page":"962","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Synthesis, Biological Evaluation, and In Silico Characterization of Novel Imidazothiadiazole\u2013Chalcone Hybrids as Multi-Target Enzyme Inhibitors"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5105-8331","authenticated-orcid":false,"given":"Hakan","family":"Alici","sequence":"first","affiliation":[{"name":"Department of Physics, Faculty of Science, Zonguldak B\u00fclent Ecevit University, 67100 Zonguldak, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Senol","family":"Topuz","sequence":"additional","affiliation":[{"name":"Department of Physics, Faculty of Science, Zonguldak B\u00fclent Ecevit University, 67100 Zonguldak, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kadir","family":"Demir","sequence":"additional","affiliation":[{"name":"Department of Physics, Faculty of Science, Zonguldak B\u00fclent Ecevit University, 67100 Zonguldak, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Parham","family":"Taslimi","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Faculty of Science, Bartin University, 74110 Bart\u0131n, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1557-6315","authenticated-orcid":false,"given":"Hakan","family":"Tahtaci","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, Karabuk University, 78050 Karabuk, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Alv\u00e1rez-Builla, J., and Barluenga, J. 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