Synthesis and Biological Evaluation of New Cholinesterase Inhibitors for Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder mostly influencing the elderly, and causes death due to dementia. The main pathogenic feature connected with the progression of this multifactorial disease is the weakening of the cholinergic system in the brain. Cholinesterase (ChE) inhibitors are recognized as one of the choices in the treatment of AD. The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were approved as a therapeutic strategy to reduce the symptoms of AD and prevent its progression. The capacity of BChE is not completely known yet; rather, it is accepted to assume a part in a few disorders such as AD. Thus, BChE inhibitors may have a greater role for the treatment of AD in the future. In the present study, 2-(9-acridinylamino)-2-oxoethyl piperazine/piperidine/morpholinecarbodithioate derivatives were synthesized in order to investigate anticholinesterase activity. Eight derivatives demonstrated a specific and promising action against BChE. Furthermore, compound 4n showed inhibitory activity against both enzymes. It was found that the active compounds were well tolerated in the cytotoxicity test. Possible interactions between the lead compound, 4n, and the BChE enzyme were determined through a docking study. The findings obtained within this paper will contribute to the development of new and effective synthetic anti-Alzheimer compounds, and will ideally encourage future screening against AD.

Design, Synthesis, and Structure–Activity Relationships of Thiazole Analogs as Anticholinesterase Agents for Alzheimer’s Disease

“…The reagents and materials used in the enzyme inhibition assay were supplied commercially from Sigma-Aldrich (St. Louis, MO, USA) and Fluka (Steinheim, Germany). The cholinesterase enzyme inhibition procedure was applied as previously reported in our research papers [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ].…”

“…Moreover, a substrate (ATC) was used at various concentrations (600, 300, 150, 75, 37.5, and 18.75 µM). The enzyme kinetics assay was carried out as in our previous publications [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. Lineweaver–Burk plots were formed using Microsoft Office Excel 2013.…”

Canine Models of Inherited Musculoskeletal and Neurodegenerative Diseases

“…There is no cure for AD and treatments are largely supportive. Most treatments consist of pharmacotherapy (cholinesterase inhibitors, NMDA antagonists) and psychosocial therapy (environmental manipulation, family support, prevention of additional medical comorbidities) (5,(20)(21)(22)(23)(24).…”

Peran Neuroprotektor Astaxanthin dalam Pencegahan Penyakit Alzheimer

“…Tidak ada obat untuk penyakit Alzheimer selain pengobatan simptomatik yang tersedia. Dua kategori obat disetujui untuk pengobatan penyakit Alzheimer yaitu: inhibitor kolinesterase dan antagonis N-metil D-aspartat (NMDA) parsial (Hussein et al, 2018). Mengingat bahwa kerusakan oksidatif dan peningkatan inflamasi saraf secara kritis terkait dengan patogenesis dari kehilangan neuron besar-besaran pada penyakit neurodegeneratif, efek neuroprotektif dari senyawa alami, seperti astaxanthin, memiliki perhatian khusus sebagai pengobatan tambahan dan pencegahan untuk penyakit ini (Cho et al, 2018).…”