Combining Experimental and Computational Methods to Produce Conjugates of Anticholinesterase and Antioxidant Pharmacophores with Linker Chemistries Affecting Biological Activities Related to Treatment of Alzheimer's Disease.

Autor: Makhaeva GF; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia., Kovaleva NV; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia., Rudakova EV; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia., Boltneva NP; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia., Lushchekina SV; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia.; Emanuel Institute of Biochemical Physics Russian Academy of Sciences, Moscow 119334, Russia., Astakhova TY; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia.; Emanuel Institute of Biochemical Physics Russian Academy of Sciences, Moscow 119334, Russia., Timokhina EN; Emanuel Institute of Biochemical Physics Russian Academy of Sciences, Moscow 119334, Russia., Serkov IV; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia., Proshin AN; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia., Soldatova YV; Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia., Poletaeva DA; Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia., Faingold II; Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia., Mumyatova VA; Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia., Terentiev AA; Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia., Radchenko EV; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia.; Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia., Palyulin VA; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia.; Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia., Bachurin SO; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia., Richardson RJ; Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI 48109, USA.; Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.; Center of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.; Michigan Institute for Computational Discovery and Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
Jazyk: angličtina
Zdroj: Molecules (Basel, Switzerland) [Molecules] 2024 Jan 09; Vol. 29 (2). Date of Electronic Publication: 2024 Jan 09.
DOI: 10.3390/molecules29020321
Abstrakt: 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 to AD treatment. Here, we report significant extensions of these studies, including the use of variable-length spacers and more detailed biological characterizations. Conjugates were potent inhibitors of acetylcholinesterase (AChE, the most active was 17d IC 50 15.1 ± 0.2 nM) and butyrylcholinesterase (BChE, the most active was 18d : IC 50 5.96 ± 0.58 nM), with weak inhibition of off-target carboxylesterase. Conjugates with alkylamine spacers were more effective cholinesterase inhibitors than alkylimine analogs. Optimal inhibition for AChE was exhibited by cyclohexaquinoline and for BChE by cycloheptaquinoline. Increasing spacer length elevated the potency against both cholinesterases. Structure-activity relationships agreed with docking results. Mixed-type reversible AChE inhibition, dual docking to catalytic and peripheral anionic sites, and propidium iodide displacement suggested the potential of hybrids to block AChE-induced β -amyloid (A β ) aggregation. Hybrids also exhibited the inhibition of A β self-aggregation in the thioflavin test; those with a hexaquinoline ring and C8 spacer were the most active. Conjugates demonstrated high antioxidant activity in ABTS and FRAP assays as well as the inhibition of luminol chemiluminescence and lipid peroxidation in mouse brain homogenates. Quantum-chemical calculations explained antioxidant results. Computed ADMET profiles indicated favorable blood-brain barrier permeability, suggesting the CNS activity potential. Thus, the conjugates could be considered promising multifunctional agents for the potential treatment of AD.
Databáze: MEDLINE
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