title: Synthesis and characterization of novel 1,2-oxazine-based small molecules that targets acetylcholinesterase.
abstract: Thirteen 2-oxazine-based small molecules were synthesized targeting 5-lipoxygenase (LOX), and acetylcholinesterase (AChE). The test revealed that the newly synthesized compounds had potent inhibition towards both 5-LOX and AChE in lower micro molar concentration. Among the tested compounds, the most active compound, 2-[(2-acetyl-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-oxazin-3-yl)methyl]-1H-isoindole-1,3(2H)-dione (2a) showed inhibitory activity towards 5-LOX and AChE with an IC50 values of 1.88, and 2.5 μM, respectively. Further, the in silico molecular docking studies revealed that the compound 2a bound to the catalytic domain of AChE strongly with a highest CDOCKER score of -1.18 kcal/mol when compared to other compounds of the same series. Additionally, 2a showed a good lipophilicity (logP=2.66), suggesting a potential ability to penetrate the blood-brain-barrier. These initial pharmacological data revealed that the compound 2a could serve as a drug-seed in developing anti-Alzheimer's agents.
authors.affiliation: N.D. Zelinsky Institute of Organic Chemistry, Leninsky Prospect, 47, Moscow 119991, Russia.
authors.forename: Alexey Yu
authors.initials: AY
authors.lastname: Sukhorukov
authors.affiliation: Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Palace Road, Bangalore 560001, India.
authors.forename: Anilkumar C
authors.initials: AC
authors.lastname: Nirvanappa
authors.affiliation: Department of Chemistry, University of Mysore, Manasagangotri, Mysore 560001, India.
authors.forename: Jagadish
authors.initials: J
authors.lastname: Swamy
authors.affiliation: N.D. Zelinsky Institute of Organic Chemistry, Leninsky Prospect, 47, Moscow 119991, Russia.
authors.forename: Sema L
authors.initials: SL
authors.lastname: Ioffe
authors.affiliation: Department of Biotechnology, Sri Jayachamarajendra College of Engineering, JSS, Technical Institutions Campus, Mysore 570006, India.
authors.forename: Shivananju
authors.initials: S
authors.lastname: Nanjunda Swamy
authors.affiliation: Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Palace Road, Bangalore 560001, India. Electronic address: salundibasappa@gmail.com.
authors.lastname: Basappa
authors.affiliation: Department of Chemistry, University of Mysore, Manasagangotri, Mysore 560001, India. Electronic address: rangappaks@gmail.com.
authors.forename: Kanchugarakoppal S
authors.initials: KS
authors.lastname: Rangappa
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D010078:Oxazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010797:Phthalimides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000595768:2-((2-acetyl-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-oxazin-3-yl)methyl)-1H-isoindole-1,3(2H)-dione; D002800:Cholinesterase Inhibitors; D016859:Lipoxygenase Inhibitors; D010078:Oxazines; D010797:Phthalimides; D054852:Small Molecule Libraries; D001094:Arachidonate 5-Lipoxygenase; D000110:Acetylcholinesterase
keywords: Acetylcholinesterase; Alzheimer disease; Chemical biology; Lipoxygenase; Oxazine