This manuscript reports the synthesis and characterization of 19 novel heterostilbene carbamates, designed as selective butyrylcholinesterase (BChE) inhibitors with potential applications in the treatment of neurodegenerative disorders, particularly Alzheimer’s disease. The compounds were synthesized from resveratrol analogs, and their structures were confirmed by NMR spectroscopy, high-resolution mass spectrometry (HRMS), and single-crystal X-ray diffraction for selected derivatives (compounds 1 and 4). In vitro assays demonstrated high selectivity toward BChE over acetylcholinesterase (AChE), with compound 16 exhibiting exceptional inhibitory activity (IC₅₀ = 26.5 nM). Furthermore, compound 16 showed moderate anti-inflammatory effects by inhibiting LPS-stimulated TNF-α production in peripheral blood mononuclear cells. In silico ADME(T) profiling revealed favorable pharmacokinetic properties and low mutagenic potential for the majority of compounds. Molecular docking and molecular dynamics simulations confirmed stable binding interactions within the BChE active site. These results highlight heterostilbene carbamates as promising lead structures for developing novel therapeutic agents targeting neurodegenerative diseases.

Background/Objectives: This research reports the synthesis and evaluation of novel charged thienobenzo-triazoles as non-selective cholinesterase inhibitors (AChEs and BChEs), their anti-inflammatory properties, and a computational study. Methods: Fifteen derivatives were created through photochemical cyclization and quaternization of the triazole core. The compounds were tested for AChE and BChE inhibition. They showed greater potency and selectivity toward BChE. Results: The most potent compound, derivative 14, inhibited BChE with an IC₅₀ of 98 nM, while derivative 9 also displayed significant anti-inflammatory activity by inhibiting LPS-induced TNF-α production (IC₅₀ = 0.66 µM). Molecular docking revealed that triazolinium salts form key π-π and electrostatic interactions within enzyme active sites. In silico predictions indicated favorable ADME-Tox properties for compounds 9 and 11, including low mutagenicity and moderate CNS permeability. Conclusions: These findings highlight the potential of new charged triazolinium salts as peripherally selective cholinesterase inhibitors with additional anti-inflammatory potential.

This manuscript reports the synthesis and characterization of 19 novel heterostilbene carbamates, designed as selective butyrylcholinesterase (BChE) inhibitors with potential application in the treatment of neurodegenerative disorders, particularly Alzheimer's disease. The compounds were synthesized from resveratrol analogs, and their structures were confirmed by NMR spectroscopy, high-resolution mass spectrometry (HRMS), and single-crystal X-ray diffraction for selected derivatives (compounds 1 and 4). In vitro assays demonstrated high selectivity toward BChE over acetylcholinesterase (AChE), with compound 16 exhibiting exceptional inhibitory activity (IC₅₀ = 26.5 nM). Furthermore, compound 16 showed moderate anti-inflammatory effects by inhibiting LPS-stimulated TNF-α production in peripheral blood mononuclear cells. In silico ADME(T) profiling revealed favorable pharmacokinetic properties and low mutagenic potential for the majority of compounds. Molecular docking and molecular dynamics simulations confirmed stable binding interactions within the BChE active site. These results highlight heterostilbene carbamates as promising lead structures for developing novel therapeutic agents targeting neurodegenerative diseases.

This study presents the synthesis and evaluation of novel charged thienoben-zo-1,2,3-triazoles as non-selective cholinesterase inhibitors (AChE and BChE), including their anti-inflammatory properties and computational analysis. Fifteen derivatives were synthesized via photochemical cyclization and triazole core quaternization. The compounds were tested for AChE and BChE inhibition, showing greater potency and selectivity toward BChE. The most potent compound, derivative 14, inhibited BChE with an IC₅₀ of 98 nM, while derivative 9 also demonstrated significant anti-inflammatory activity by inhibiting LPS-induced TNF-α production (IC₅₀ = 0.66 µM). Molecular docking revealed that triazolium salts form key π-π and electrostatic interactions within enzyme active sites. In silico predictions indicated favorable ADME-Tox properties for compounds 9 and 11, including low mutagenicity and moderate CNS permeability. These results highlight the potential of novel charged triazoles as peripherally selective cholinesterase inhibitors with added anti-inflammatory effects.

Resveratrol-inspired methoxy-substituted pyrrolidine- and morpholine-based carba-mates bearing oxazole or benzimidazole moieties were synthesized and evaluated for their cholinesterase-inhibitory and anti-inflammatory activities. A series of twelve compounds (1–12) was prepared and structurally characterized using spectroscopic methods. Their inhibitory activities against acetylcholinesterase (AChE) and butyryl-cholinesterase (BChE) were determined using a modified Ellman assay, while an-ti-inflammatory activity was assessed by measuring TNF-α production in lipopolysac-charide-stimulated human peripheral blood mononuclear cells. The investigated com-pounds selectively inhibited BChE, while showing weak or negligible inhibition of AChE. Pyrrolidine-based oxazole carbamate 1 exhibited the highest BChE inhibitory potency (IC₅₀ = 0.09 μM), approximately 25-fold greater than standard rivastigmine. Compound 1 was also the only tested derivative to concentration-dependently inhibit TNF-α production (IC₅₀ = 4.3 μM) without affecting cell viability. Molecular docking of compounds 1 and 9, the best pyrrolidine- and morpholine-based carbamates, indicated that both fit within the BChE active-site gorge through extensive aromatic, hydrophobic, and polar interactions. Overall, the results identify compound 1 as a promising multi-functional lead for further investigation of the relationship between cholinesterase in-hibition and anti-inflammatory activity.

Resveratrol-inspired methoxy-substituted pyrrolidine- and morpholine-based carbamates bearing oxazole or benzimidazole moieties were synthesized and evaluated for their cholinesterase-inhibitory and anti-inflammatory activities. A series of twelve compounds (1–12) was prepared and structurally characterized using spectroscopic methods. Their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were determined using a modified Ellman assay, while anti-inflammatory activity was assessed by measuring TNF-α production in lipopolysaccharide-stimulated human peripheral blood mononuclear cells. The investigated compounds selectively inhibited BChE, while showing weak or negligible inhibition of AChE. Pyrrolidine-based oxazole carbamate 1 exhibited the highest BChE inhibitory potency (IC₅₀ = 0.09 μM), approximately 25-fold greater than standard rivastigmine. Compound 1 was also the only tested derivative to concentration-dependently inhibit TNF-α production (IC₅₀ = 4.3 μM) without affecting cell viability. Molecular docking of compounds 1 and 9, the best pyrrolidine- and morpholine-based carbamates, indicated that both fit within the BChE active-site gorge through extensive aromatic, hydrophobic, and polar interactions. Overall, the results identify compound 1 as a promising multifunctional lead for further investigation of the relationship between cholinesterase inhibition and anti-inflammatory activity.