Abstract
A series of novel 2-carbo–substituted 5-oxo-5H-furo[3,2-g]chromene-6-carbaldehydes and their 6-(4-trifluoromethyl)phenylhydrazono derivatives have been prepared and evaluated for biological activity against the human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The most active compounds from each series were, in turn, evaluated against the following enzyme targets involved in Alzheimer’s disease, β-secretase (BACE-1) and lipoxygenase-15 (LOX-15), as well as for anti-oxidant potential. Based on the in vitro results of ChE and β-secretase inhibition, the kinetic studies were conducted to determine the mode of inhibition by these compounds. 2-(4-Methoxyphenyl)-5-oxo-5H-furo[3,2-g]chromene-6-carbaldehyde (2f), which exhibited significant inhibitory effect against all these enzymes was also evaluated for activity against the human lipoxygenase-5 (LOX-5). The experimental results were complemented with molecular docking into the active sites of these enzymes. Compound 2f was also found to be cytotoxic against the breast cancer MCF-7 cell line.
Highlights
The World Health Organization (WHO) has predicted that neurodegenerative diseases (NDs) that mainly affect the motor functions will overtake cancer to become the second-most prevalent cause of death after cardiovascular diseases [1,2]
In an attempt to address the complexity of Alzheimer‘s disease (AD), it has become necessary to design and develop drugs with increased potency capable of controlling multiple targets involved in this disease at the same time
A combination of 3-fluorophenyl- group at the C-2 position of the furan moiety and a 6-carbaldehyde functionality resulted in significant inhibitory effect of 2b against cholinesterases and moderate activity against β-secretase and lipoxygenase-15 accompanied by increased anti-oxidant effect
Summary
The World Health Organization (WHO) has predicted that neurodegenerative diseases (NDs) that mainly affect the motor functions will overtake cancer to become the second-most prevalent cause of death after cardiovascular diseases [1,2]. LOX-5 inhibitors, for example, reduce neuro-inflammation, amyloid plaques and neurofibrillary tangles, which are hallmarks of Alzheimer’s disease [8]. In an attempt to address the complexity of AD, it has become necessary to design and develop drugs with increased potency capable of controlling multiple targets involved in this disease at the same time. This multi-target-directed ligand design strategy has been found to be more effective for the treatment of AD [14,15]. It reduces the risk associated with poor patient compliance, drug–drug interactions and pharmacokinetic differences between the individual drugs
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