Polypharmacological Approaches for CNS Diseases: Focus on Endocannabinoid Degradation Inhibition

Cells, Journal Year: 2022, Volume and Issue: 11(3), P. 471 - 471

Published: Jan. 29, 2022

Polypharmacology breaks up the classical paradigm of "one-drug, one target, disease" electing multitarget compounds as potential therapeutic tools suitable for treatment complex diseases, such metabolic syndrome, psychiatric or degenerative central nervous system (CNS) disorders, and cancer. These diseases often require a combination therapy which may result in positive but also negative synergistic effects. The endocannabinoid (ECS) is emerging particularly attractive target CNS disorders neurodegenerative including Parkinson's disease (PD), Alzheimer's (AD), Huntington's (HD), multiple sclerosis (MS), amyotrophic lateral (ALS), stroke, traumatic brain injury (TBI), pain, epilepsy. ECS an organized neuromodulatory network, composed by endogenous cannabinoids, cannabinoid receptors type 1 2 (CB1 CB2), main catabolic enzymes involved inactivation fatty acid amide hydrolase (FAAH) monoacylglycerol lipase (MAGL). connections with other signaling pathways allows consideration optimal source inspiration development innovative polypharmacological compounds. In this review, we focused our attention on reported examples FAAH MAGL inhibitors are involved.

Language: Английский

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Conjugates of Tacrine and Salicylic Acid Derivatives as New Promising Multitarget Agents for Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2285 - 2285

Published: Jan. 24, 2023

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: IC50 values lead compound 10c 0.0826 µM 0.0156 (BChE), weak off-target carboxylesterase. mixed-type reversible both cholinesterases displayed dual binding catalytic peripheral anionic sites in molecular docking, which, along experimental results propidium iodide displacement, suggested their potential block AChE-induced β-amyloid aggregation. inhibited Aβ42 self-aggregation thioflavin test, Salicylimine 5c (CH2)8 spacers compounds for inhibiting self-aggregation, which corroborated docking Aβ42. ABTS•+-scavenging activity highest salicylamides 5a–c, intermediate salicylimines 10a–c, low F-containing 7, non-existent methoxybenzoylamides 6 difluoromethoxybenzoylamides 8. In FRAP antioxidant (AO) assay, test or no Quantum chemical analysis dynamics (MD) simulations QM/MM potentials explained AO structure–activity relationships. effective chelators Cu2+, Fe2+, Zn2+, molar compound/metal (Cu2+) ratios 2:1 (5b) ~1:1 (10b). Conjugates comparable lower cytotoxicity than mouse hepatocytes had favorable predicted intestinal absorption blood-brain barrier permeability. overall indicate that are promising multifunctional agents treatment AD.

Language: Английский

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Enhancing the Therapeutic Effect in Alzheimer's Disease Drugs: The role of Polypharmacology and Cholinesterase inhibitors

ChemistrySelect, Journal Year: 2023, Volume and Issue: 8(10)

Published: March 7, 2023

Abstract Alzheimer's disease (AD) is a devastating syndrome that accounts for 60–70 % of all dementia cases, putting an enormous burden on global healthcare and economy. Unfortunately, there no cure AD, the currently approved drugs are limited in their effects. Given various pathological mechanisms behind “one‐target, one‐drug” paradigm drug design became obsolete, new paradigm, polypharmacology, emerged. Consequently, greater focus has been put towards multi‐target directed ligands (MTDLs), as these can regulate several targets operating network. Parallel to that, cholinesterase inhibitors have regained popularity after decades being considered only symptomatic agents with disease‐modifying properties. In this review, current AD hypotheses therapeutic targets, concept polypharmacology pathology importance cholinesterases pathogenesis biochemical processes discussed, final overview development cholinesterase‐based MTDLs.

Language: Английский

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New Multifunctional Agents Based on Conjugates of 4-Amino-2,3-polymethylenequinoline and Butylated Hydroxytoluene for Alzheimer’s Disease Treatment

Molecules, Journal Year: 2020, Volume and Issue: 25(24), P. 5891 - 5891

Published: Dec. 12, 2020

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- tetrahydro-6H-cyclohepta[b]quinolin-11-ylamino)-ethylimino]-methyl}-phenol exhibited an IC50(AChE) = 1.90 ± 0.16 µM, IC50(BChE) 0.084 0.008 13.6 1.2% propidium displacement at 20 μM. Compounds possessed low activity against carboxylesterase, indicating likely absence clinically unwanted drug-drug interactions. Kinetics consistent mixed-type reversible inhibition both cholinesterases. Docking indicated binding catalytic peripheral AChE sites; site along suggest block AChE-induced β-amyloid aggregation, a disease-modifying effect. demonstrated high antioxidant in ABTS FRAP assays well luminol chemiluminescence lipid peroxidation mouse brain homogenates. Conjugates 8 amine-containing better antioxidants than those enamine 7. Computational ADMET profiles all predicted good blood-brain barrier distribution (permeability), intestinal absorption, medium cardiac toxicity risk. Overall, based on their favorable pharmacological profiles, conjugates appear promising candidates AD therapeutics.

Language: Английский

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Amiridine-piperazine hybrids as cholinesterase inhibitors and potential multitarget agents for Alzheimer's disease treatment

Bioorganic Chemistry, Journal Year: 2021, Volume and Issue: 112, P. 104974 - 104974

Published: May 21, 2021

Language: Английский

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