Abstract
Alzheimer’s disease (AD), a progressive neurodegenerative disorder, characterized by central cognitive dysfunction, memory loss, and intellectual decline poses a major public health problem affecting millions of people around the globe. Despite several clinically approved drugs and development of anti-Alzheimer’s heterocyclic structural leads, the treatment of AD requires safer hybrid therapeutics with characteristic structural and biochemical properties. In this endeavor, we herein report a microwave-assisted synthesis of a library of quinoline thiosemicarbazones endowed with a piperidine moiety, achieved via the condensation of 6/8-methyl-2-(piperidin-1-yl)quinoline-3-carbaldehydes and (un)substituted thiosemicarbazides. The target N-heterocyclic products were isolated in excellent yields. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, 1H- and 13C-NMR). Anti-Alzheimer potential of the synthesized heterocyclic compounds was evaluated using acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vitro biochemical assay results revealed several compounds as potent inhibitors of both enzymes. Among them, five compounds exhibited IC50 values less than 20 μM. N-(3-chlorophenyl)-2-((8-methyl-2-(piperidin-1-yl)quinolin-3-yl)methylene)hydrazine carbothioamide emerged as the most potent dual inhibitor of AChE and BChE with IC50 values of 9.68 and 11.59 μM, respectively. Various informative structure–activity relationship (SAR) analyses were also concluded indicating the critical role of substitution pattern on the inhibitory efficacy of the tested derivatives. In vitro results were further validated through molecular docking analysis where interactive behavior of the potent inhibitors within the active pocket of enzymes was established. Quinoline thiosemicarbazones were also tested for their cytotoxicity using MTT assay against HepG2 cells. Among the 26 novel compounds, there were five cytotoxical and 18 showed proliferative properties.
Highlights
Alzheimer’s, known as senile dementia, is a chronic neurodegenerative disease and is a global health problem due to its limited available treatments
The results presented showed that the novel 6- and 8-methyl-2-(piperidin1-yl)quinolin-3-yl)methylene)hydrazine-1-carbothioamide derivatives are promising inhibitors of cholinesterases
The synthesized compounds contain a substantial degree of structural variation in the form of electron-donating as well as electron-withdrawing groups on different positions of the aromatic rings
Summary
Alzheimer’s, known as senile dementia, is a chronic neurodegenerative disease and is a global health problem due to its limited available treatments. The development mechanism of Alzheimer’s disease (AD) still remains elusive though multiple factors have been proposed for its induction out of which cholinergic hypothesis explains in the best manner [1]. The diminution of acetylcholine level causes cognitive deficit and memory loss. The inhibition of acetylcholinesterase (AChE; EC 3.1.1.7). Butyrylcholinesterase (BChE; EC 3.1.1.8) is supposed to be beneficial for the treatment of AD [2]. The AChE enzyme hydrolyzes the neurotransmitter (acetylcholine) to acetic acid and choline resulting in reduction of its levels that is the main cause of AD [3] while BChE hydrolyzes butyrylcholine (BuCh).
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