Lead optimization studies towards the discovery of novel carbamates as potent AChE inhibitors for the potential treatment of Alzheimer’s disease

Roy, Kuldeep K.; Tota, Santoshkumar; Tripathi, Tusha; Chander, Subhash; Nath, Chandishwar; Saxena, Anil Kumar

doi:10.1016/j.bmc.2012.09.005

Cited by 30 publications

(16 citation statements)

References 37 publications

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“…Novel donepezil-tacrine and oxoisoaporphine-tacrine congeners hybrid related derivatives, coumarin and huperzine A derivatives have exhibited high AChE inhibitory activity with IC 50 values in the nanomolar range, and ability to bind simultaneously to both peripheral and catalytic sites of the enzyme. For the reason, these dual binding site inhibitors are promising compounds for developing disease-modifying drugs for the future treatment of AD [58-62], Additionally, new synthesized symmetrical bispyridinium and carbamate anti-AChE compounds inhibit the enzyme in micromolar concentrations, making them the potential candidates for the treatment of AD [63, 64]. …”

Section: Acetylcholinesterase Inhibitorsmentioning

confidence: 99%

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

et al. 2013

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Acetylcholinesterase is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous systems. The enzyme inactivation, induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission. Hence, acetylcholinesterase inhibitors, interacting with the enzyme as their primary target, are applied as relevant drugs and toxins. This review presents an overview of toxicology and pharmacology of reversible and irreversible acetylcholinesterase inactivating compounds. In the case of reversible inhibitors being commonly applied in neurodegenerative disorders treatment, special attention is paid to currently approved drugs (donepezil, rivastigmine and galantamine) in the pharmacotherapy of Alzheimer’s disease, and toxic carbamates used as pesticides. Subsequently, mechanism of irreversible acetylcholinesterase inhibition induced by organophosphorus compounds (insecticides and nerve agents), and their specific and nonspecific toxic effects are described, as well as irreversible inhibitors having pharmacological implementation. In addition, the pharmacological treatment of intoxication caused by organophosphates is presented, with emphasis on oxime reactivators of the inhibited enzyme activity administering as causal drugs after the poisoning. Besides, organophosphorus and carbamate insecticides can be detoxified in mammals through enzymatic hydrolysis before they reach targets in the nervous system. Carboxylesterases most effectively decompose carbamates, whereas the most successful route of organophosphates detoxification is their degradation by corresponding phosphotriesterases.

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Section: Acetylcholinesterase Inhibitorsmentioning

confidence: 99%

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

et al. 2013

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“…36 Recently pyridonepezil and 6-chloro-pyridonepezil (the hybrid of donepezil and aminopyridine) have been reported to be more potent cholinesterase inhibitors than the single donepezil molecule through various in silico and in vitro studies. These compounds are considered to be dual inhibitors as they bind to both the catalytic site and the PAS.…”

Section: Conventional Drug Target Network In Ad Acetylcholinesterasementioning

confidence: 99%

“…35 One group has demonstrated that certain pyridopyrimidine derivatives have approximately 2e2.5 folds higher AChE inhibitory activity than the drug galantamine, demonstrated through the in vitro enzyme assay. 36 Certain pyridonepezil derivatives have been shown to be better and selective AChE inhibitors than the reference compound donepezil. 37 One recent study proposed that derivatives of 4-hydroxycoumarins displayed significant AChE inhibitory activity.…”

Section: Tau Proteinmentioning

confidence: 99%

Current and novel therapeutic molecules and targets in Alzheimer's disease

Kumar

Nisha

Silakari

et al. 2016

Journal of the Formosan Medical Association

127

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Alzheimer's disease (AD) is a neurodegenerative disorder in which the death of brain cells causes memory loss and cognitive decline, i.e., dementia. The disease starts with mild symptoms and gradually becomes severe. AD is one of the leading causes of mortality worldwide. Several different hallmarks of the disease have been reported such as deposits of β-amyloid around neurons, hyperphosphorylated tau protein, oxidative stress, dyshomeostasis of bio-metals, low levels of acetylcholine, etc. AD is not simple to diagnose since there is no single diagnostic test for it. Pharmacotherapy for AD currently provides only symptomatic relief and mostly targets cognitive revival. Computational biology approaches have proved to be reliable tools for the selection of novel targets and therapeutic ligands. Molecular docking is a key tool in computer-assisted drug design and development. Docking has been utilized to perform virtual screening on large libraries of compounds, and propose structural hypotheses of how the ligands bind with the target with lead optimization. Another potential application of docking is optimization stages of the drug-discovery cycle. This review summarizes the known drug targets of AD, in vivo active agents against AD, state-of-the-art docking studies done in AD, and future prospects of the docking with particular emphasis on AD.

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“…Further applications of covalent docking with GOLD have been reported to investigate covalent binding of the soman stereoisomers to human serum albumin; in lead optimization of carbamates as AChE inhibitor; to virtually screen for 20S proteasome inhibitors; and to identify key interactions of two maleimide derivatives as non‐nucleoside inhibitors of DNA methyltransferases (cf. Table for an overview of covalent‐docking applications).…”

Section: Modeling Covalent Bond Formation In Docking Approachesmentioning

confidence: 99%

Docking of Covalent Ligands: Challenges and Approaches

Sotriffer

2018

Molecular Informatics

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Covalent ligands have recently regained considerable attention in drug discovery. The rational design of such ligands, however, is still faced with particular challenges, mostly related to the fact that covalent bond formation is a quantum mechanical phenomenon which cannot adequately be handled by the force fields or empirical approaches typically used for noncovalent protein-ligand interactions. Although the necessity for quantum chemical approaches is clear, they cannot yet routinely be applied on large data sets of ligands or for a broader exploration of binding modes in docking calculations. On the other hand, technical solutions for performing docking calculations with covalent ligands are available, but their scope is normally quite limited. Scoring functions typically neglect the contribution from covalent bond formation completely. In this situation, the question arises how to approach covalent ligands and which methods to choose for their docking and design.

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Lead optimization studies towards the discovery of novel carbamates as potent AChE inhibitors for the potential treatment of Alzheimer’s disease

Cited by 30 publications

References 37 publications

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

Current and novel therapeutic molecules and targets in Alzheimer's disease

Docking of Covalent Ligands: Challenges and Approaches

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