Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer's Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis.

Sumera Zaib,Muhammad Tayyab Younas,Rubina Munir,Hashem O Alsaab,Aliya Ibrar,Noorma Shahid,Sehar Aqsa,Tahira Tasneem Asif,Imtiaz Khan,Naghmana Kausar

doi:10.3390/molecules26216573

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. The limited pharmacological approaches based on cholinesterase inhibitors only provide symptomatic relief to AD patients. Moreover, the adverse side effects such as nausea, vomiting, loss of appetite, muscle cramps, and headaches associated with these drugs and numerous clinical trial failures present substantial limitations on the use of medications and call for a detailed insight of disease heterogeneity and development of preventive and multifactorial therapeutic strategies on urgent basis. In this context, we herein report a series of quinoline-thiosemicarbazone hybrid therapeutics as selective and potent inhibitors of cholinesterases. A facile multistep synthetic approach was utilized to generate target structures bearing multiple sites for chemical modifications and establishing drug-receptor interactions. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, 1H- and 13C-NMR). In vitro inhibitory results revealed compound 5b as a promising and lead inhibitor with an IC50 value of 0.12 ± 0.02 μM, a 5-fold higher potency than standard drug (galantamine; IC50 = 0.62 ± 0.01 μM). The synergistic effect of electron-rich (methoxy) group and ethylmorpholine moiety in quinoline-thiosemicarbazone conjugates contributes significantly in improving the inhibition level. Molecular docking analysis revealed various vital interactions of potent compounds with amino acid residues and reinforced the in vitro results. Kinetics experiments revealed the competitive mode of inhibition while ADME properties favored the translation of identified inhibitors into safe and promising drug candidates for pre-clinical testing. Collectively, inhibitory activity data and results from key physicochemical properties merit further research to ensure the design and development of safe and high-quality drug candidates for Alzheimer’s disease.

Highlights

Alzheimer’s disease (AD), a chronic neurodegenerative disorder, is the leading cause of senile dementia
The ethyl chain between the morpholine and thioamide group showed peaks near 40.8 and 53.5 ppm, the former carbon signals were overlapped by NMR solvent signal (DMSO-d6)
Hybridization of quinoline carbaldehydes with thiosemicarbazides afforded target compounds in excellent yields, devoiding the need of column chromatographic purification

Summary

Introduction

Alzheimer’s disease (AD), a chronic neurodegenerative disorder, is the leading cause of senile dementia. The typical symptoms include the memory dysfunction, cognitive impairment, psychiatric and behavioral abnormality, and difficulty in performing everyday tasks [1,2,3] This multifaceted neurodegenerative disorder is one of the leading causes of death in elderly people and continues to be a social, health and economic burden on society. The exact molecular mechanism for the pathogenesis of AD is not well-understood yet; several hypotheses have been proposed explaining the initiation of neurodegeneration in Alzheimer’s disease These include cholinergic hypothesis (pathological changes and the dysfunction of the neuro-cholinergic system), amyloid hypothesis (β-amyloid tangles and aggregations inducing neural apoptosis, tau protein hyperphosphorylation forming senile plaque), oxidative stress hypothesis (neuro-inflammation and increasing level of reactive oxygen radicals), and bio-metal hypothesis (deregulation of transition bio-metals in AD patients). The design and development of new and potent inhibitors based on central cholinergic hypothesis remains the most common and clinically tested strategy for AD therapy [4,5,6,7,8]

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