Çakmak, ReşitBaşaran, EyüpErcan, SelamiBoğa, MehmetÇınar, ErcanTopal, Giray2025-02-222025-02-2220250022-2860https://doi.org/10.1016/j.molstruc.2025.141474https://hdl.handle.net/11468/29868In this research, we designed and synthesized a series of new 3- or 4-(trifluoromethyl)- substituted sulfonate esters (1–14) linked heterocyclic Schiff base derivatives (15–28) as potential inhibitors of acetylcholinesterase and butyrylcholinesterase. The chemical structures of the target compounds were elucidated using elemental analysis and various spectral techniques. In vitro inhibitory results revealed IC50 values ranging from 12.05±0.10 to 43.08±0.20 μM against acetylcholinesterase and 0.42±0.04 to 95.52±0.00 μM against butyrylcholinesterase. Among the tested compounds, most sulfonates were found to inhibit acetylcholinesterase better than butyrylcholinesterase. In contrast, their Schiff base derivatives inhibited butyrylcholinesterase more effectively acetylcholinesterase did. Compounds 19, 20, and 21 inhibited butyrylcholinesterase better than galanthamine. The effects of trifluoromethyl group at positions 3 or 4 of the sulfonate moiety and the biosubstitutions at position R2 of the spacer moiety on the inhibitory activities were evaluated. Moreover, the antioxidant potency of these compounds was assessed by three different assays (DPPH free radical scavenging activity, ABTS cationic radical decolorization, and cupric reducing antioxidant capacity. The newly synthesized derivatives showed very low antioxidant activity (>1000 μM) in the DPPH and ABTS assays, while some of 3- trifluoromethyl substituted Schiff base derivatives (compounds 15, 20, and 21) showed activity closer to α-tocopherol in cupric reducing antioxidant capacity assay. The binding modes and binding free energies for acetylcholinesterase and butyrylcholinesterase inhibitor candidates were determined through docking studies. Taken together, we consider some inhibitor candidates to be valuable lead structures that can be used in further studies to design new anti-Alzheimer's disease drugs. © 2025 Elsevier B.V.eninfo:eu-repo/semantics/closedAccessAntioxidant activityAntipyrineCholinesterase inhibitoryMolecular dockingSchiff baseArticle13292-s2.0-8521535923610.1016/j.molstruc.2025.141474Q1