title: Novel Tacrine-Benzofuran Hybrids as Potent Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease: Design, Synthesis, Biological Evaluation, and X-ray Crystallography.
abstract: 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.
authors.affiliation: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, P. R. China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zha
authors.affiliation: Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Area Science Park - Basovizza , S.S. no. 14 Km 163.5, I-34149 Trieste, Italy.
authors.forename: Doriano
authors.initials: D
authors.lastname: Lamba
authors.affiliation: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, P. R. China.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, P. R. China.
authors.forename: Yinghan
authors.initials: Y
authors.lastname: Lou
authors.affiliation: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, P. R. China.
authors.forename: Changxu
authors.initials: C
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, P. R. China.
authors.forename: Di
authors.initials: D
authors.lastname: Kang
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Yungen
authors.initials: Y
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, P. R. China.
authors.forename: Luyong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department for Life Quality Studies, University of Bologna , Corso d'Augusto 237, I-47921 Rimini, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: De Simone
authors.affiliation: Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Area Science Park - Basovizza , S.S. no. 14 Km 163.5, I-34149 Trieste, Italy.|Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Trieste , Via L. Giorgieri 1, I-34127 Trieste, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: Samez
authors.affiliation: Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Area Science Park - Basovizza , S.S. no. 14 Km 163.5, I-34149 Trieste, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pesaresi
authors.affiliation: Institute of Biochemistry, Medical Faculty, University of Ljubljana , Vrazov trg 2, SI-1000 Ljubljana, Slovenia.
authors.forename: Jure
authors.initials: J
authors.lastname: Stojan
authors.affiliation: Instituto Teófilo Hernando, Department of Pharmacology, Universidad Autónoma de Madrid , C/Arzobispo Morcillo 4, 28029 Madrid, Spain.
authors.forename: Manuela G
authors.initials: MG
authors.lastname: Lopez
authors.affiliation: Instituto Teófilo Hernando, Department of Pharmacology, Universidad Autónoma de Madrid , C/Arzobispo Morcillo 4, 28029 Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Egea
authors.affiliation: Department for Life Quality Studies, University of Bologna , Corso d'Augusto 237, I-47921 Rimini, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna , Via Belmeloro 6, I-40126 Bologna, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Bartolini
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors; D001522:Behavior, Animal / Q000187:drug effects; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D018697:Nootropic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014101:Torpedo
chemical_list: D001572:Benzofurans; D002800:Cholinesterase Inhibitors; D018697:Nootropic Agents; D013619:Tacrine; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human