Abstract
To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a new series of 1,2,3-triazole-chromenone derivatives were designed and synthesized based on the multi target-directed ligands approach. The in vitro biological activities included acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition as well as anti-Aβ aggregation, neuroprotective effects, and metal-chelating properties. The results indicated a highly selective BuChE inhibitory activity with an IC50 value of 21.71 μM for compound 10h as the most potent compound. Besides, compound 10h could inhibit self-induced Aβ1–42 aggregation and AChE-induced Aβ aggregation with 32.6% and 29.4% inhibition values, respectively. The Lineweaver–Burk plot and molecular modeling study showed that compound 10h targeted both the catalytic active site (CAS) and peripheral anionic site (PAS) of BuChE. It should be noted that compound 10h was able to chelate biometals. Thus, the designed scaffold could be considered as multifunctional agents in AD drug discovery developments.
Highlights
Dementia is one of the noteworthy problems in the public health management as over 80% of dementia cases are suffering from Alzheimer’s disease (AD)
Molecular docking evaluation of compound A depicted that coumarin moiety interacted with Trp231 and Phe329 residues of catalytic active site (CAS) pocket and benzyl pyridinium moiety interacted with Trp82 of BuChE peripheral anionic site (PAS) pocket [20]
According to the interaction mode of compound B, it can be understood that 1,2,3-triazole-aryl moiety led to the formation of hydrophobic interactions with amino acids of PAS and chromenone ring oriented towards CAS pocket [21]
Summary
Dementia is one of the noteworthy problems in the public health management as over 80% of dementia cases are suffering from Alzheimer’s disease (AD). Available therapies provide temporary symptomatic relief but do not target the distractive neuropathology. A new treatment to delay or halt disease progression has remained as an urgent medical need. The pathophysiological processes in AD have still remained unclear to this day. Alongside its complexity, several neurodegenerative processes could. Based on the approved theory for AD, the loss of cholinergic neurons causes reduction of ACh. As a result, inhibition of the acetylcholinesterase (AChE) raises the level of ACh and improves cognitive performance
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
