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, antioxidant properties have been calculated from ORAC assays. Furthermore, studies of anti-inflammatory properties 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 Aβ-induced cell death in human neuroblastoma SH-SY5Y cells with antioxidant properties.

Calmodulin Binding Domains in Critical Risk Proteins Involved in Neurodegeneration

“…AS105, GS-680, and RA306 are ATP-competitive inhibitors of activated CaMKII, while KN-93 is an allosteric inhibitor of CaM binding to inactive CaMKII [ 63 ]. Currently, drugs that affect more than one target (e.g., BACE1 and AchR) have been developed, suggesting that this approach could be viable for co-targeting more than one specific CaMBP [ 64 ]. Other approaches to regulating CaMKII function (e.g., antisense oligonucleotides, small interfering RNA, and miRNAs) are also under analysis [ 63 ].…”