Abstract
A novel series of coumarin derivatives linked to the N-benzyl triazole group were synthesized and evaluated against 15-lipoxygenase (15-LOX), and acetyl- and butyrylcholinesterase (AChE and BuChE) to find the most potent derivative against Alzheimer’s disease (AD). Most of the compounds showed weak to moderate activity against ChEs. Among the most active BuChE and 15-LOX inhibitors, 8l and 8n exhibited an excellent neuroprotective effect, higher than the standard drug (quercetin) on the PC12 cell model injured by H2O2 and significantly reduced aggregation of amyloid Aβ1-42, with potencies of 1.44 and 1.79 times higher than donepezil, respectively. Compound 8l also showed more activity than butylated hydroxytoluene (BHT) as the reference antioxidant agent in reducing the levels of H2O2 activated by amyloid β in BV2 microglial cells. Kinetic and ligand–enzyme docking studies were also performed for better understanding of the mode of interaction between the best BuChE inhibitor and the enzyme. Considering the acceptable BuChE and 15-LOX inhibition activities as well as significant neuroprotection, and anti-amyloid aggregation activities, 8l and 8n could be considered as potential MTDLs for further modification and studies against AD.
Highlights
Alzheimer’s disease (AD) is a type of age-related and progressive neurodegenerative disorder leading to severe cognitive and psychiatric impairment in elderly individuals
We aimed to make a balance between the biological activities of the target compounds to reach to the multi-target–directed ligand (MTDL), even having mild activity against one or several targets instead of finding one-target compounds with high affinity
A novel series of benzyl triazole–arylcoumarin hybrids were synthesized as multi-target–directed ligands (MTDLs) against AD
Summary
Alzheimer’s disease (AD) is a type of age-related and progressive neurodegenerative disorder leading to severe cognitive and psychiatric impairment in elderly individuals. Multifactorial cause of AD requires a multi-target approach for the treatment Such an approach can be achieved through the combination of effective pharmacophoric groups in a unique small molecule. Drug combination therapies for the treatment of AD lead to more beneficial therapeutic effects and resulted in the superior in vivo outcomes compared to the one-target compounds having high affinity, even if the multi-target small molecules have mild activity against one or several targets (Morphy and Rankovic, 2007). Preliminary docking studies encouraged us to conjugate the 3-arylcoumarin scaffold to N-benzyl triazole fragments as the well-known pharmacophoric groups playing crucial role in anti-ChE activity (Figure 1) (Kiani et al, 2019). The main aim of this study was to endow the 3-arylcoumarin backbone with more inhibition activities through conjugation with N-benzyl triazoles to find the optimum multi-target small molecules against AD
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