Design, synthesis and biological activity evaluation for discovery of novel acetylcholinesterase inhibitors in Alzheimer's Disease

Abstract

Dementia is a major global public health challenge facing the current generation. More than 35 million people worldwide are living with the disease and this number will double by 2030 and triple by 2050. Alzheimer's disease (AD) is the most common form of dementia and this neurodegenerative disease is characterised by a slow, progressive and irreversible process loss of cognitive function and memory. Some neuropathological features have been identified and characterised, such as the presence of amyloid plaque (deposition of amyloid-² protein fragments) and neurofibrillary tangles (coiled wire Tau protein) associated with progressive loss of memory and cognitive function as a result of cholinergic depletion. The current standard treatment for mild to moderate stages of AD involves increased cholinergic transmission by inhibiting the enzyme acetylcholinesterase (AChE). Indeed, cholinesterase inhibitors are the most promising drugs developed to date, it is the only therapeutic class that showed improvement in cognitive function in patients with AD. Some AChE inhibitors, known as dual inhibitors (interact both in the active site and peripheral site), generally have been developed based on classical AChE inhibitors such as tacrine (Cognex ®) and donepezil (Aricept ®). The success of the strategy involving dual inhibitors is a result of considerable increase in the enzyme inhibition regarding to the parent compounds. Thus, this project will address the strategy to synthesise dual inhibitors via "click chemistry" and peptidomimetic, which are emerging and relevant concepts in the discovery of bioactive molecules. In addition, these strategies have been well explored by the candidate during postdoctoral research in the UK. It is important to highlight that this project will be part of FAPESP/CSIC project (process 2013/50788-3) entitled "Novel potential anti-Alzheimer agents: from design to preclinical studies" and under supervision of Professor Ivone Carvalho (Brazil) and Professor Ana Martinez Gil (Spain). Therefore, the initial objectives of this project involve i) synthesis of a library of compounds with potential to bind both the active and peripheral sites of AChE (dual inhibitors), ii) molecular modelling studies (methods of docking simulations, bioisosteric replacement and molecular dynamics) in order to lead to the rational design of inhibitors with higher affinity and iii) biological activity evaluation of the synthesised compounds (AChE inhibition assay and inhibition of amyloid-² peptide aggregation induced by AChE). Preliminary molecular modelling studies involving the docking simulations of some designed compounds in this project were promising, suggesting their potential to interact with the entire extension of the active and peripheral sites of AChE. (AU)