Abstract
A series of multi-target directed edaravone derivatives bearing N-benzyl pyridinium moieties were designed and synthesised. Edaravone is a potent antioxidant with significant neuroprotective effects and N-benzyl pyridinium has previously exhibited positive results as part of a dual-site binding, peripheral anionic site (PAS) and catalytic anionic site (CAS), acetylcholinesterase (AChE) inhibitor. The designed edaravone-N-benzyl pyridinium hybrid compounds were docked within the AChE active site. The results indicated interactions with conserved amino acids (Trp279 in PAS and Trp84 in CAS), suggesting good dual-site inhibitory activity. Significant in vitro AChE inhibitory activities were observed for selected compounds (IC50: 1.2–4.6 µM) with limited butyrylcholinesterase inhibitory activity (IC50’s >160 µM), indicating excellent selectivity towards AChE (SI: 46 – >278). The compounds also showed considerable antioxidant ability, similar to edaravone. In silico studies indicated that these compounds should cross the blood–brain barrier, making them promising lead molecules in the development of anti-Alzheimer’s agents.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is mainly prevalent in the older population (>65 years of age)[1–3]
To determine if the edaravone portion of the hybrid molecules would exhibit the proposed interactions with the peripheral anionic site (PAS) as well as potential interactions exhibited by the Nbenzyl pyridinium moiety with the catalytic anionic site (CAS), molecular docking studies were performed
The molecular modelling results showed that these compounds should be able to form significant interactions within the PAS and CAS of the AChE active site, which in turn should lead to notable inhibitory activities
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is mainly prevalent in the older population (>65 years of age)[1–3]. The primary constituent of these senile plaques is Ab and are believed to play a central role in the pathogenesis of the disease[6,7]. The APP mutations are situated near the sites where proteases, b and c-secretase, cleave the APP. These mutations result in the favouring of the Ab1–40 and Ab1–42 peptide fragment formation[7,8,10]. With the persistent imbalance of the production and clearance of the Ab fragments, the consequential result is the genesis of insoluble senile plaques. These senile plaques result in the blockage of parenchymal spaces between neurons in the brain leading to eventual neuronal cell death[8,9]
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