A5079521426- Cholinesterase and Neurodegenerative Diseases
- Computational Drug Discovery Methods
- Pesticide Exposure and Toxicity
- Synthesis and biological activity
- Protein Structure and Dynamics
- Enzyme Structure and Function
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Chemical Reaction Mechanisms
- Free Radicals and Antioxidants
- Synthesis and bioactivity of alkaloids
- Enzyme function and inhibition
- Nicotinic Acetylcholine Receptors Study
- Pesticide and Herbicide Environmental Studies
- Chemical synthesis and alkaloids
- Chemistry and Chemical Engineering
- Alzheimer's disease research and treatments
- bioluminescence and chemiluminescence research
- Biochemical Acid Research Studies
- Amino Acid Enzymes and Metabolism
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Click Chemistry and Applications
- Pharmacogenetics and Drug Metabolism
- Environmental Toxicology and Ecotoxicology
- Medicinal Plants and Neuroprotection
Institute of Biochemical Physics NM Emanuel
2015-2024
Weizmann Institute of Science
2024
Institute of Physiologically Active Compounds
2015-2024
A.E. Arbuzov Institute of Organic and Physical Chemistry
2015-2016
Lomonosov Moscow State University
2010-2015
Russian Academy of Sciences
2009-2014
Abstract Alzheimer disease is a multifactorial pathology and the development of new multitarget neuroprotective drugs promising attractive. We synthesized group original compounds, which combine in one molecule γ-carboline fragment dimebon phenothiazine core methylene blue (MB) linked by 1-oxo- 2-hydroxypropylene spacers. Inhibitory activity conjugates toward acetylcholinesterase (AChE), butyrylcholinesterase (BChE) structurally close to them carboxylesterase (CaE), as well their binding...
Organophosphorus agents (OPs) are irreversible inhibitors of acetylcholinesterase (AChE). OP poisoning causes major cholinergic syndrome. Current medical counter-measures mitigate the acute effects but have limited action against OP-induced brain damage. Bioscavengers appealing alternative therapeutic approach because they neutralize OPs in bloodstream before reach physiological targets. First generation bioscavengers stoichiometric bioscavengers. However, neutralization requires...
A new group of compounds, promising for the design original multitarget therapeutic agents treating neurodegenerative diseases, based on conjugates aminoadamantane and carbazole derivatives was synthesized investigated. Compounds these series were found to interact with a targets that play an important role in development this type diseases. First all, compounds selectively inhibit butyrylcholinesterase, block NMDA receptors containing NR2B subunits while maintaining properties MK-801...
A series of previously synthesized conjugates tacrine and salicylamide was extended by varying the structure fragment using salicylic aldehyde to synthesize salicylimine derivatives. The hybrids exhibited broad-spectrum biological activity. All new were potent inhibitors acetylcholinesterase (AChE) butyrylcholinesterase (BChE) with selectivity toward BChE. moiety exerted little effect on anticholinesterase activity, but AChE inhibition increased spacer elongation. most active derivatives:...
CSP (cresyl saligenin phosphate) is an irreversible inhibitor of human BChE (butyrylcholinesterase) that has been involved in the aerotoxic syndrome. Inhibition under pseudo-first-order conditions biphasic, reflecting a slow equilibrium between two enzyme states E and E′. The elementary constants for inhibition wild-type D70G mutant were determined by studying dependence kinetics on viscosity osmotic pressure. Glycerol sucrose used as viscosogens. Phosphorylation sensitive to thus strongly...
New hybrids of 4-amino-2,3-polymethylenequinoline with different sizes the aliphatic ring linked to butylated hydroxytoluene (BHT) by enaminoalkyl (7) or aminoalkyl (8) spacers were synthesized as potential multifunctional agents for Alzheimer’s disease (AD) treatment. All compounds potent inhibitors acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) selectivity toward BChE. Lead compound 8c, 2,6-di-tert-butyl-4-{[2-(7,8,9,10-...
Effective therapeutics for Alzheimer's disease (AD) are in great demand worldwide. In our previous work, we responded to this need by synthesizing novel drug candidates consisting of 4-amino-2,3-polymethylenequinolines conjugated with butylated hydroxytoluene via fixed-length alkylimine or alkylamine linkers (spacers) and studying their bioactivities pertaining AD treatment. Here, report significant extensions these studies, including the use variable-length spacers more detailed biological...
Organisms evolve mechanisms that regulate the properties of biogenic crystals to support a wide range functions, from vision and camouflage communication thermal regulation. Yet, mechanism underlying formation diverse intracellular remains enigmatic. Here we unravel biochemical control over crystal morphogenesis in zebrafish iridophores. We show chemical composition determines their shape, particularly through ratio between nucleobases guanine hypoxanthine. reveal these variations are...
Inhibition of human AChE (acetylcholinesterase) and BChE (butyrylcholinesterase) by an alkylammonium derivative 6-methyluracil, C-547, a potential drug for the treatment MG (myasthenia gravis) was studied. Kinetic analysis inhibition showed that C-547 is slow-binding inhibitor type B, i.e. after formation initial enzyme·inhibitor complex (Ki=140 pM), induced-fit step allows establishment final (Ki*=22 pM). The estimated koff low, 0.05 min(-1) On other hand, reversible fast-binding process...
New hybrid compounds of 4-amino-2,3-polymethylene-quinoline containing different sizes the aliphatic ring and linked to p-tolylsulfonamide with alkylene spacers increasing length were synthesized as potential drugs for treatment Alzheimer’s disease (AD). All potent inhibitors acetylcholinesterase (AChE) butyrylcholinesterase (BChE) selectivity toward BChE. The lead compound 4-methyl-N-(5-(1,2,3,4-tetrahydro-acridin-9-ylamino)-pentyl)-benzenesulfonamide (7h) exhibited an IC50 = 0.131 ± 0.01...
Abstract In arthropods, zinc finger-associated domains (ZADs) are found at the N-termini of many DNA-binding proteins with tandem arrays Cys2-His2 fingers (ZAD-C2H2 proteins). ZAD-C2H2 undergo fast evolutionary lineage-specific expansion and functional diversification. Here, we show that all ZADs from Drosophila melanogaster form homodimers, but only certain high homology can also heterodimerize. CG2712, for example, is unable to heterodimerize its paralog, previously characterized insulator...
Butyrylcholinesterase deficiency is characterized by prolonged apnea after the use of muscle relaxants (suxamethonium or mivacurium) in patients who have mutations BCHE gene. Here, we report a case neuromuscular block administration suxamethonium leading to discovery novel variant (c.695T>A, p.Val204Asp). Inhibition studies, kinetic analysis and molecular dynamics were undertaken understand how this mutation disrupts catalytic triad determines "silent" phenotype. Low activity patient plasma...
Abstract Novel 6‐methyluracil derivatives with ω‐(substituted benzylethylamino)alkyl chains at the nitrogen atoms of pyrimidine ring were designed and synthesized. The numbers methylene groups in alkyl varied along electron‐withdrawing substituents on benzyl rings. compounds are mixed‐type reversible inhibitors cholinesterases, some them show remarkable selectivity for human acetylcholinesterase (hAChE), inhibitory potency nanomolar range, more than 10 000‐fold higher that...