Design and synthesis of benzodiazepine-1,2,3-triazole hybrid derivatives as selective butyrylcholinesterase inhibitors
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ORIGINAL ARTICLE
Design and synthesis of benzodiazepine‑1,2,3‑triazole hybrid derivatives as selective butyrylcholinesterase inhibitors Mehrdad Mehrazar1 · Mahdi Hassankalhori2 · Mahsa Toolabi3 · Fereshteh Goli1 · Setareh Moghimi1 · Hamid Nadri4 · Syed Nasir Abbas Bukhari5 · Loghman Firoozpour1 · Alireza Foroumadi3,6 Received: 20 June 2019 / Accepted: 18 October 2019 © Springer Nature Switzerland AG 2019
Abstract A new series of compounds based on benzodiazepine-1,2,3-triazole were synthesized and evaluated as cholinesterase inhibitors by Ellman’s method. The compounds proved to be selective inhibitors of butyrylcholinesterase (BuChE) over acetylcholinesterase. The most potent compound was 3,3-dimethyl-11-(3-((1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methoxy) phenyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one, identified as a submicromolar inhibitor of BuChE with IC50 value of 0.2 µM. In addition, the amyloid-β self-aggregation evaluation studies for selected compounds showed potent inhibitory effects compared to donepezil. The docking and cell viability studies supported the potential of compound 9b-6 as significant BuChE inhibitor. Graphic abstract
Keywords Alzheimer’s disease · Benzodiazepine · 1,2,3-Triazole · Butyrylcholinesterase inhibitor · Click chemistry Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11030-019-10008-x) contains supplementary material, which is available to authorized users. * Loghman Firoozpour [email protected] * Alireza Foroumadi [email protected] Extended author information available on the last page of the article
Introduction Dementia is one of the most widespread illnesses, affecting the lives of millions of people around the world [1–3]. Alzheimer’s disease (AD) is a neurodegenerative, chronic, and progressive disease, associated with losses of mental capabilities in terms of memory and learning. These disabilities gradually lead to the tragic isolation of an individual
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due to the inability of communication with other people and the world. AD accounts for nearly 70% of dementia cases in people 65 years of age or older and classified as the apparent consequence of brain cells death especially pyramidal cells [4]. The tremendous impact on abilities of people with this disease has urged the needs for persistent care by family members and (un)paid caregivers along with expensive therapies. Accordingly, to both reduce economic consequences of the disease on society and increase the life expectancy in an old population, a growing budget should be applied to develop novel treatment approaches [5, 6]. There are different hypotheses about the causes of this destruction process including: protein aggregation, ROS production, oxidative stress, mitochondrial dysfunction, neuroinflammation, and cholinergic depletion. Protein aggregation is the biochemical process which led to the formation of abnormal protein within and outside of the brain cells including senile plaques and neurofibrillary
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