Lin_2026_Bioorg.Med.Chem.Lett__130716

A series of chalcone hybrids including benzoylpiperazin (phenylacetylpiperazin)-thiophene were designed, synthesized and evaluated their inhibitory activities against cholinesterase (ChE). All compounds displayed good inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among them, compound 2e displayed the most inhibitory activity against AChE, BChE and beta-amyloid (Abeta(42)) with IC(50) values 7.01, 5.39 and 4.47 microM, respectively. Meanwhile, 2e was found anti-Alzheimer's disease (AD) effect by significantly alleviating lipopolysaccharide (LPS)/Abeta-induced neurotoxicity, reducing the levels of reactive oxygen species (ROS), pro-inflammatory cytokines, and exert anti-inflammatory effects by regulating the NF-kappaB (Nuclear factor kappa-light-chain-enhancer of activated B cells) pathway. Furthermore, the molecular modeling studies showed that 2e target both catalytic active site as well as peripheral anionic site of AChE, BChE and Abeta(42), and possess strong bind affinity. In addition, in silico ADMET and toxicity predictions demonstrated favorable oral absorption and potential blood-brain barrier (BBB) permeability for 2e. The rationale remains partly overstated. The novelty claim should more precisely distinguish this scaffold from previously reported chalcone, piperazine, thiophene, and multitarget ChE/Abeta inhibitors. The phrase "anti-Alzheimer's agents" should be softened, because the data are limited to enzyme assays, Abeta assays, BV-2 cellular models, docking, and computational predictions.