Design, synthesis and evaluation of vilazodone-tacrine hybrids as multitarget-directed ligands against depression with cognitive impairment

Liu, Wenwen; Wang, Huan; Li, Xiaokang; Xu, Yixiang; Zhang, Jian; Wang, Wei; Gong, Qi; Qiu, Xiaoxia; Zhu, Jin; Mao, Fei; Zhang, Haiyan; Li, Jian

doi:10.1016/j.bmc.2018.04.037

Cited by 20 publications

(9 citation statements)

References 45 publications

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“…Original research on novel tacrine derivatives has been still carrying out. Since the original drafting of our review, a few important publications have appeared: Cen et al 2018;Chioua et al 2018;Hamulakova et al 2018;Hepnarova et al 2018;Hiremathad et al 2018;Jiang et al 2018;Liu et al 2018;Skibiński et al 2017;Wu et al 2018.…”

Section: Discussionmentioning

confidence: 99%

Tacrine hybrids as multi-target-directed ligands in Alzheimer’s disease: influence of chemical structures on biological activities

Girek

2018

Chem. Pap.

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Alzheimer's disease is a neurological disorder, which is the most common form of dementia affecting mostly elderly people. The number of patients is still rapidly increasing which results in negative impacts on population. The loss of cholinergic transmission is one of the signs of Alzheimer's disease; it is connected with cognition impairment and memory loss. Therefore, some drug therapies are based on restoring the cholinergic function. Therefore, drug therapies are based on the cholinergic hypothesis. Acetylcholinesterase inhibitors such as donepezil, galantamine, and rivastigmine are nowadays in medical use. Tacrine possesses a simple structure and strong activity, but despite these features, it was withdrawn from the market due to its side effects. Due to the multifactorial etiology of Alzheimer's disease, researchers have investigated multitarget-directed ligands based on tacrine structure to achieve better treatment efficacy. To broaden the therapeutic profile of the ligands, tacrine is bound to numerous moieties with various applications. The hybrids can be obtained in three ways: first, by conjugating; second, by fusing; third, by merging single molecules. The hybrids can target numerous disease pathways simultaneously. This is a promising concept, which will create multiple drugs that will minimize the symptoms of diseases in elderly populations. In this review, we will be describing differently synthesized series of tacrine compounds which were divided based on their biological activities.

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Section: Discussionmentioning

confidence: 99%

Tacrine hybrids as multi-target-directed ligands in Alzheimer’s disease: influence of chemical structures on biological activities

Girek

2018

Chem. Pap.

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“…Some methods for the modification of tacrine focused on tacrine scaffolds such as benzene rings or hexane rings. ,, In addition to this, multifunctional tacrine hybrids have been the most widely studied tacrine derivatives . Tacrine was conjugated with different moieties such as lophine, melatonin, 8-hydroxyquinoline, chromenes, coumarin, NO donor groups, caffeic acid, propargylamine, β-carboline, vilazodone, and carbohydrates to provide the effective MTDL strategy for the improvement of the therapeutic application of tacrine. − The representative hybrids were bis( n )-tacrine linked by an alkylene chain, as reported by Pang et al, which were up to 1000-fold more potent than tacrine since they have double interactions in the cholinesterase with both CAS and PAS . Since then, the 9-NH 2 group has been a key site for synthesizing tacrine analogues .…”

Section: Introductionmentioning

confidence: 99%

Late-Stage Modification of Medicine: Pd-Catalyzed Direct Synthesis and Biological Evaluation of N-Aryltacrine Derivatives

Wan

Zhen

et al. 2021

ACS Omega

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A new series of N -aryltacrine derivatives were designed and synthesized as cholinesterase inhibitors by the late-stage modification of tacrine, using the palladium-catalyzed Buchwald–Hartwig cross-coupling reaction. In vitro inhibition assay against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) demonstrated that most of the synthesized compounds had potent AChE inhibitory activity with negative inhibition of BuChE. Among them, N -(4-(trifluoromethyl)phenyl)-tacrine ( 3g ) and N -(4-methoxypyridin-2-yl)-tacrine ( 3o ) showed the most potent activity against AChE (IC 50 values of 1.77 and 1.48 μM, respectively). The anti-AChE activity of 3g and 3o was 3.5 times more than that of tacrine (IC 50 value of 5.16 μM). Compound 3o also displayed anti-BuChE activity with an IC 50 value of 19.00 μM. Cell-based assays against HepG2 and SH-SY5Y cell lines revealed that 3o had significantly lower hepatotoxicity compared to tacrine, with additional neuroprotective activity against H 2 O 2 -induced damage in SH-SY5Y cells. The advantages including synthetic accessibility, high potency, low toxicity, and adjunctive neuroprotective activity make compound 3o a new promising multifunctional candidate for the treatment of Alzheimer’s disease.

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“…Due to the similar properties of 3a and 3b, the difficulty of product purification increases, and the total yield of the route reduces. After this, many scientific researchers have made improvements and optimizations on the basis of this route, − but the corresponding impurities will inevitably be produced. The total yield of the route and product purity remain the existing challenges.…”

Section: Introductionmentioning

confidence: 99%

Practical and Scalable Manufacturing Process for a Novel Dual-Acting Serotonergic Antidepressant Vilazodone

Jin

Zhou

et al. 2021

Org. Process Res. Dev.

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Vilazodone combines the effects of a selective serotonin reuptake inhibitor with the 5-HT1A receptor partial agonist activity. Here, we report the development of a viable and scalable process for manufacturing vilazodone that features a convergent synthetic approach, with low cost and high purity. The key indole synthesis was improved to first make up the hydrazone intermediate and then modify a pendant hydroxy group to realize a much increased overall yield. This process was successfully used to prepare >2 kg of vilazodone hydrochloride with a total yield of 56.2% and purity of 99.93%.

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Design, synthesis and evaluation of vilazodone-tacrine hybrids as multitarget-directed ligands against depression with cognitive impairment

Cited by 20 publications

References 45 publications

Tacrine hybrids as multi-target-directed ligands in Alzheimer’s disease: influence of chemical structures on biological activities

Tacrine hybrids as multi-target-directed ligands in Alzheimer’s disease: influence of chemical structures on biological activities

Late-Stage Modification of Medicine: Pd-Catalyzed Direct Synthesis and Biological Evaluation of N-Aryltacrine Derivatives

Practical and Scalable Manufacturing Process for a Novel Dual-Acting Serotonergic Antidepressant Vilazodone

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