{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:39:09Z","timestamp":1791362349217,"version":"4.3.1"},"reference-count":69,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:00:00Z","timestamp":1769644800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Research Fund of Ad\u0131yaman University","award":["ECZMAP\/2023-0002"],"award-info":[{"award-number":["ECZMAP\/2023-0002"]}]},{"name":"Research Fund of Ad\u0131yaman University","award":["ECZMAP\/2023-0004"],"award-info":[{"award-number":["ECZMAP\/2023-0004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Pyrazole carboxamides are widely used as adaptable medicinal-chemistry scaffolds and have been explored as cholinesterase (ChE) inhibitor chemotypes. In this work, we prepared a new series of 4-arylazo-3,5-diamino-N-tosyl-1H-pyrazole-1-carboxamides 5(a\u2013m) and evaluated their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), supported by structure-based computational analyses. Methods: Thirteen derivatives 5(a\u2013m) were synthesized, fully characterized with analytical techniques (FT-IR, H NMR, and C NMR), and tested in vitro against AChE and BChE, with tacrine (THA) used as the reference inhibitor. Docking calculations were used to examine plausible binding modes. The top-ranked complexes (7XN1\u20135e and 4BDS\u20135i) were further examined by 100 ns explicit-solvent molecular dynamics (MD) simulations in Cresset Flare, followed by RMSD\/RMSF analysis and contact-persistence profiling. Predicted ADME\/Tox. properties were also assessed to identify potential developability issues. Results: The series showed strong ChE inhibition, and several compounds were more potent than THA. Compound 5e (4-nitro) was the most active AChE inhibitor (KI = 20.86 \u00b1 1.61 nM) compared with THA (KI = 164.40 \u00b1 20.84 nM). For BChE, the KI values ranged from 31.21 to 87.07 nM and exceeded the reference compound\u2019s activity. MD trajectories supported stable binding in both systems (10\u2013100 ns mean backbone RMSD: 2.21 \u00b1 0.17 \u00c5 for 7XN1\u20135e; 1.89 \u00b1 0.11 \u00c5 for 4BDS\u20135i). Most fluctuations were confined to flexible regions, while key contacts remained in place, consistent with the docking models. ADME\/Tox. predictions suggested moderate lipophilicity but generally low aqueous solubility; all compounds were predicted as non-BBB permeant, and selected liabilities were flagged (e.g., carcinogenicity for 5e\/5g\/5h\/5i; nephrotoxicity for 5f\/5g). Conclusions: The 4-arylazo-3,5-diamino-N-tosyl-1H-pyrazole-1-carboxamide scaffold delivers low-nanomolar ChE inhibition, with docking and MD supporting stable binding modes. Future optimization should prioritize solubility improvement and mitigation of predicted toxicities and metabolic liabilities, especially given the predicted lack of BBB permeability for CNS-directed applications.<\/jats:p>","DOI":"10.3390\/ph19020239","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T08:19:38Z","timestamp":1769761178000},"page":"239","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Design and Synthesis of 4-Arylazo Pyrazole Carboxamides as Dual AChE\/BChE Inhibitors: Kinetic and In Silico Evaluation"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4506-5265","authenticated-orcid":false,"given":"Suleyman","family":"Akocak","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ad\u0131yaman University, Ad\u0131yaman 02040, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nebih","family":"Lolak","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ad\u0131yaman University, Ad\u0131yaman 02040, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2080-0091","authenticated-orcid":false,"given":"Hatice Esra","family":"Duran","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Faculty of Medicine, Kafkas University, Kars 36100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9926-107X","authenticated-orcid":false,"given":"B\u00fc\u015fra","family":"Demir \u00c7etinkaya","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Erzincan Binali Y\u0131ld\u0131r\u0131m University, Erzincan 24002, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8649-7534","authenticated-orcid":false,"given":"Hamada","family":"Hashem","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sohag University, Sohag 82524, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4845-3191","authenticated-orcid":false,"given":"Stefan","family":"Br\u00e4se","sequence":"additional","affiliation":[{"name":"Institute of Biological and Chemical Systems Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, 76131 Karlsruhe, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2932-2789","authenticated-orcid":false,"given":"C\u00fcneyt","family":"T\u00fcrke\u015f","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy, Erzincan Binali Y\u0131ld\u0131r\u0131m University, Erzincan 24002, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"(2024). 2024 Alzheimer\u2019s disease facts and figures. 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