👤 Marija Bartolić

β-Secretase (BACE1) is the key enzyme responsible for generating amyloid-β (Aβ) peptides, whose aggregation and plaque formation are major hallmarks of Alzheimer's disease (AD). Owing to its central role in Aβ production, BACE1 has become a widely studied therapeutic target in the search for disease-modifying treatments for AD. However, evidence of numerous physiological substrates indicates that BACE1 participates in diverse biological processes, from the development and maintenance of the nervous system through control of neuronal differentiation and axonal myelination to immune response mediation by promotion of cell-cell interactions. These functions prompted research into the enzyme's role in other neurodegenerative disorders such as Parkinson's disease, Niemann-Pick type C disease, and Creutzfeldt-Jakob disease, whose pathophysiology includes aberrant protein aggregation and/or cognitive decline leading to dementia as seen in AD, as well as in neurological conditions such as schizophrenia and epilepsy, which are characterized by impaired neurotransmission and seizures, respectively. This review summarizes current knowledge on BACE1 substrates involved in nervous system regulation and immune response, highlights its roles at the molecular and genetic levels across aforementioned disorders, and outlines outcomes from clinical trials of BACE1 inhibitors. Show less

The growing prevalence of Alzheimer's disease calls for a drug that can simultaneously act towards several targets involved in the pathophysiology of the disease. In our study, we evaluated the potential of hydrazone and Show less

Alzheimer's disease is age-related multifactorial neurodegenerative disease manifested by gradual loss of memory, cognitive decline and changes in personality. Due to rapid and continuous growth of its prevalence, the treatment of Alzheimer's disease calls for development of new and efficacies drugs, especially those that could be able to simultaneously act on more than one of possible targets of action. Aminoquinolines have proven to be a highly promising structural scaffold in the design of such a drug as cholinesterases and β-secretase 1 inhibitors. In this study, we synthesised twenty-two new 4-aminoquinolines with different halogen atom and its position in the terminal N-benzyl group or with a trifluoromethyl or a chlorine as C(7)-substituents on the quinoline moiety. All compounds were evaluated as multi-target-directedligands by determining their inhibition potency towards human acetylcholinesterase, butyrylcholinesterase and β-secretase 1. All of the tested derivatives were very potent inhibitors of human acetylcholinesterase and butyrylcholinesterase with inhibition constants (K Show less

The most successful therapeutic strategy in the treatment of Alzheimer's disease (AD) is directed toward increasing levels of the neurotransmitter acetylcholine (ACh) by inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), the enzymes responsible for its hydrolysis. In this paper, we extended our study on 4-aminoquinolines as human cholinesterase inhibitors on twenty-six new 4-aminoquinolines containing an n-octylamino spacer on C(4) and different substituents on the terminal amino group. We evaluated the potency of new derivatives to act as multi-targeted ligands by determining their inhibition potency towards human AChE and BChE, ability to chelate biometals Fe, Cu and Zn, ability to inhibit the action of β-secretase 1 (BACE1) and their antioxidant capacity. All of the tested derivatives were very potent inhibitors of human AChE and BChE with inhibition constants (K Show less