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J Med Chem. 2016 Jan 14;59(1):114-31. doi: 10.1021/acs.jmedchem.5b01119. Epub 2015 Dec 29.

Novel Tacrine-Benzofuran Hybrids as Potent Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease: Design, Synthesis, Biological Evaluation, and X-ray Crystallography.

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State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, P. R. China.
Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Area Science Park - Basovizza , S.S. no. 14 Km 163.5, I-34149 Trieste, Italy.
Department for Life Quality Studies, University of Bologna , Corso d'Augusto 237, I-47921 Rimini, Italy.
Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Trieste , Via L. Giorgieri 1, I-34127 Trieste, Italy.
Institute of Biochemistry, Medical Faculty, University of Ljubljana , Vrazov trg 2, SI-1000 Ljubljana, Slovenia.
Instituto Teófilo Hernando, Department of Pharmacology, Universidad Autónoma de Madrid , C/Arzobispo Morcillo 4, 28029 Madrid, Spain.
Department of Pharmacy and Biotechnology, University of Bologna , Via Belmeloro 6, I-40126 Bologna, Italy.


Twenty-six new tacrine-benzofuran hybrids were designed, synthesized, and evaluated in vitro on key molecular targets for Alzheimer's disease. Most hybrids exhibited good inhibitory activities on cholinesterases and β-amyloid self-aggregation. Selected compounds displayed significant inhibition of human β-secretase-1 (hBACE-1). Among the 26 hybrids, 2e showed the most interesting profile as a subnanomolar selective inhibitor of human acetylcholinesterase (hAChE) (IC50 = 0.86 nM) and a good inhibitor of both β-amyloid aggregation (hAChE- and self-induced, 61.3% and 58.4%, respectively) and hBACE-1 activity (IC50 = 1.35 μM). Kinetic studies showed that 2e acted as a slow, tight-binding, mixed-type inhibitor, while X-ray crystallographic studies highlighted the ability of 2e to induce large-scale structural changes in the active-site gorge of Torpedo californica AChE (TcAChE), with significant implications for structure-based drug design. In vivo studies confirmed that 2e significantly ameliorates performances of scopolamine-treated ICR mice. Finally, 2e administration did not exhibit significant hepatotoxicity.

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