Abstract
In view of the multifactorial nature of Alzheimer’s disease (AD), multitarget small molecules (MTSM) represent the most potent and attractive therapeutic strategy to design new drugs for Alzheimer’s disease therapy. The new MTSM KojoTacrines (KTs) were designed and synthesized by juxtaposition of selected pharmacophoric motifs from kojic acid and tacrine. Among them, 11-amino-2-(hydroxymethyl)-12-(3-methoxyphenyl)-7,9,10,12-tetrahydropyrano [2',3':5,6] pyrano[2,3-b]quinolin-4(8H)-one (KT2d) was identified as less-hepatotoxic than tacrine, at higher concentration, a moderate, but selective human acetylcholinesterase inhibitor (IC50 = 4.52 ± 0.24 µM), as well as an antioxidant agent (TE = 4.79) showing significant neuroprotection against Aβ1–40 at 3 µM and 10 µM concentrations. Consequently, KT2d is a potential new hit-ligand for AD therapy for further biological exploration.
Highlights
The World Health Organization claims that 46 million people worldwide suffer from Alzheimer’s disease (AD)
Because of the complex nature of AD, multitarget small molecules (MTSM), able to interact simultaneously with the different enzymatic systems or receptors involved in the pathology, have emerged as one of the most promising therapeutic strategies in order to design and identify new drugs for AD10–15
We have prepared a number of new MTSM by multicomponent reactions (MCR)[16,17,18,19] as acetylcholinesterase inhibitors (AChEIs), showing neuroprotective effect and strong antioxidant activity
Summary
The World Health Organization claims that 46 million people worldwide suffer from Alzheimer’s disease (AD). Because of the complex nature of AD, multitarget small molecules (MTSM), able to interact simultaneously with the different enzymatic systems or receptors involved in the pathology, have emerged as one of the most promising therapeutic strategies in order to design and identify new drugs for AD10–15 Following this paradigm, we have prepared a number of new MTSM by multicomponent reactions (MCR)[16,17,18,19] as AChEIs, showing neuroprotective effect and strong antioxidant activity. 11-amino-2(hydroxymethyl)-12–(3-methoxyphenyl)-7,9,10,12-tetrahydropyrano[2’, 3’:5,6]pyrano[2,3-b]quinolin-4(8H)-one (KT2d) was identified as a hitagent, less hepatotoxic than tacrine, completely selective against AChE, showing potent antioxidant properties and displaying a very significant neuroprotection against amyloid beta (Ab)
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