Synthesis, Biological Evaluation, and In Silico Characterization of Novel Imidazothiadiazole–Chalcone Hybrids as Multi-Target Enzyme Inhibitors
<b>Background/Objectives:</b> The need for dual-targeted enzyme inhibitors is critical in addressing complex diseases like Alzheimer’s and glaucoma. Imidazothiadiazole and chalcone moieties are known for diverse bioactivities. This study aimed to develop novel imidazothiadiazole–chalcone...
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MDPI AG
2025-06-01
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| author | Hakan Alici Senol Topuz Kadir Demir Parham Taslimi Hakan Tahtaci |
| author_facet | Hakan Alici Senol Topuz Kadir Demir Parham Taslimi Hakan Tahtaci |
| author_sort | Hakan Alici |
| collection | DOAJ |
| description | <b>Background/Objectives:</b> The need for dual-targeted enzyme inhibitors is critical in addressing complex diseases like Alzheimer’s and glaucoma. Imidazothiadiazole and chalcone moieties are known for diverse bioactivities. This study aimed to develop novel imidazothiadiazole–chalcone hybrids as potential inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase isoforms (hCAs), specifically hCA I and hCA II. <b>Methods:</b> Four hybrid molecules (<b>8a–8d</b>) were synthesized and structurally confirmed via <sup>1</sup>H NMR, <sup>13</sup>C NMR, FT-IR, MS, and elemental analysis techniques. Their enzyme inhibitory activities were assessed using Ellman’s and Verpoorte’s 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. <b>Results:</b> All compounds showed strong enzyme inhibition: AChE (K<sub>i</sub>: 3.86–11.35 nM), BChE (K<sub>i</sub>: 1.01–1.78 nM), hCA I (K<sub>i</sub>: 45.13–81.24 nM), and hCA II (K<sub>i</sub>: 36.08–52.45 nM). Docking analyses confirmed favorable binding, particularly with active-site residues. MD simulations demonstrated stable interactions throughout 100 ns. Compound <b>8a</b> exhibited the highest cholinesterase inhibition, while compounds <b>8d</b> and <b>8c</b> 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. <b>Conclusions:</b> These findings suggest that imidazothiadiazole–chalcone 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. |
| format | Article |
| id | doaj-art-b11c703fe0e342e8b64164034e8df0fb |
| institution | Kabale University |
| issn | 1424-8247 |
| language | English |
| publishDate | 2025-06-01 |
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| spelling | doaj-art-b11c703fe0e342e8b64164034e8df0fb2025-08-20T03:56:47ZengMDPI AGPharmaceuticals1424-82472025-06-0118796210.3390/ph18070962Synthesis, Biological Evaluation, and In Silico Characterization of Novel Imidazothiadiazole–Chalcone Hybrids as Multi-Target Enzyme InhibitorsHakan Alici0Senol Topuz1Kadir Demir2Parham Taslimi3Hakan Tahtaci4Department of Physics, Faculty of Science, Zonguldak Bülent Ecevit University, 67100 Zonguldak, TürkiyeDepartment of Physics, Faculty of Science, Zonguldak Bülent Ecevit University, 67100 Zonguldak, TürkiyeDepartment of Physics, Faculty of Science, Zonguldak Bülent Ecevit University, 67100 Zonguldak, TürkiyeDepartment of Biotechnology, Faculty of Science, Bartin University, 74110 Bartın, TürkiyeDepartment of Chemistry, Faculty of Science, Karabuk University, 78050 Karabuk, Türkiye<b>Background/Objectives:</b> The need for dual-targeted enzyme inhibitors is critical in addressing complex diseases like Alzheimer’s and glaucoma. Imidazothiadiazole and chalcone moieties are known for diverse bioactivities. This study aimed to develop novel imidazothiadiazole–chalcone hybrids as potential inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase isoforms (hCAs), specifically hCA I and hCA II. <b>Methods:</b> Four hybrid molecules (<b>8a–8d</b>) were synthesized and structurally confirmed via <sup>1</sup>H NMR, <sup>13</sup>C NMR, FT-IR, MS, and elemental analysis techniques. Their enzyme inhibitory activities were assessed using Ellman’s and Verpoorte’s 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. <b>Results:</b> All compounds showed strong enzyme inhibition: AChE (K<sub>i</sub>: 3.86–11.35 nM), BChE (K<sub>i</sub>: 1.01–1.78 nM), hCA I (K<sub>i</sub>: 45.13–81.24 nM), and hCA II (K<sub>i</sub>: 36.08–52.45 nM). Docking analyses confirmed favorable binding, particularly with active-site residues. MD simulations demonstrated stable interactions throughout 100 ns. Compound <b>8a</b> exhibited the highest cholinesterase inhibition, while compounds <b>8d</b> and <b>8c</b> 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. <b>Conclusions:</b> These findings suggest that imidazothiadiazole–chalcone 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.https://www.mdpi.com/1424-8247/18/7/962imidazothiadiazolechalcone hybridscarbonic anhydrase inhibitorsacetylcholinesterase inhibitorsbutyrylcholinesterase inhibitorsmolecular docking |
| spellingShingle | Hakan Alici Senol Topuz Kadir Demir Parham Taslimi Hakan Tahtaci Synthesis, Biological Evaluation, and In Silico Characterization of Novel Imidazothiadiazole–Chalcone Hybrids as Multi-Target Enzyme Inhibitors Pharmaceuticals imidazothiadiazole chalcone hybrids carbonic anhydrase inhibitors acetylcholinesterase inhibitors butyrylcholinesterase inhibitors molecular docking |
| title | Synthesis, Biological Evaluation, and In Silico Characterization of Novel Imidazothiadiazole–Chalcone Hybrids as Multi-Target Enzyme Inhibitors |
| title_full | Synthesis, Biological Evaluation, and In Silico Characterization of Novel Imidazothiadiazole–Chalcone Hybrids as Multi-Target Enzyme Inhibitors |
| title_fullStr | Synthesis, Biological Evaluation, and In Silico Characterization of Novel Imidazothiadiazole–Chalcone Hybrids as Multi-Target Enzyme Inhibitors |
| title_full_unstemmed | Synthesis, Biological Evaluation, and In Silico Characterization of Novel Imidazothiadiazole–Chalcone Hybrids as Multi-Target Enzyme Inhibitors |
| title_short | Synthesis, Biological Evaluation, and In Silico Characterization of Novel Imidazothiadiazole–Chalcone Hybrids as Multi-Target Enzyme Inhibitors |
| title_sort | synthesis biological evaluation and in silico characterization of novel imidazothiadiazole chalcone hybrids as multi target enzyme inhibitors |
| topic | imidazothiadiazole chalcone hybrids carbonic anhydrase inhibitors acetylcholinesterase inhibitors butyrylcholinesterase inhibitors molecular docking |
| url | https://www.mdpi.com/1424-8247/18/7/962 |
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