Multitarget drugs as potential therapeutic agents for alzheimer’s disease. A new family of 5-substituted indazole derivatives as cholinergic and BACE1 inhibitors

Abstract

Multitarget drugs are a promising therapeutic approach against Alzheimer’s disease. In this work, a new family of 5-substituted indazole derivatives with a multitarget profile including cholinesterase and BACE1 inhibition is described. Thus, the synthesis and evaluation of a new class of 5-substituted indazoles has been performed. Pharmacological evaluation includes in vitro inhibitory assays on AChE/BuChE and BACE1 enzymes. Also, the corresponding competition studies on BuChE were carried out. Additionally, antioxi- dant properties have been calculated from ORAC assays. Furthermore, studies of anti-inflammatory proper- ties on Raw 264.7 cells and neuroprotective effects in human neuroblastoma SH-SY5Y cells have been performed. The results of pharmacological tests have shown that some of these 5-substituted indazole derivatives 1–4 and 6 behave as AChE/BuChE and BACE1 inhibitors, simultaneously. In addition, some indazole derivatives showed anti-inflammatory (3, 6) and neuroprotective (1–4 and 6) effects against Ab- induced cell death in human neuroblastoma SH-SY5Y cells with antioxidant properties.This work was supported from Ministerio de Economía, Industria y Competitividad, Gobierno de Espa~na under Grant RTI2018-096100B-100.Peer reviewe