155628-03-8Relevant articles and documents
Development of acetophenone ligands as potential neuroimaging agents for cholinesterases
Jollymore-Hughes, Courtney T.,Pottie, Ian R.,Martin, Earl,Rosenberry, Terrone L.,Darvesh, Sultan
, p. 5270 - 5279 (2016)
Association of cholinesterase with β-amyloid plaques and tau neurofibrillary tangles in Alzheimer's disease offers an opportunity to detect disease pathology during life. Achieving this requires development of radiolabelled cholinesterase ligands with high enzyme affinity. Various fluorinated acetophenone derivatives bind to acetylcholinesterase with high affinity, including 2,2,2-trifluoro-1-(3-dimethylaminophenyl)ethanone (1) and 1-(3-tert-butylphenyl)-2,2,2-trifluoroethanone (2). Such compounds also offer potential for incorporation of radioactive fluorine (18F) for Positron Emission Tomography (PET) imaging of cholinesterases in association with Alzheimer's disease pathology in the living brain. Here we describe the synthesis of two meta-substituted chlorodifluoroacetophenones using a Weinreb amide strategy and their rapid conversion to the corresponding trifluoro derivatives through nucleophilic substitution by fluoride ion, in a reaction amenable to incorporating18F for PET imaging. In vitro kinetic analysis indicates tight binding of the trifluoro derivatives to cholinesterases. Compound 1 has a Kivalue of 7?nM for acetylcholinesterase and 1300?nM for butyrylcholinesterase while for compound 2 these values are 0.4?nM and 26?nM, respectively. Tight binding of these compounds to cholinesterase encourages their development for PET imaging detection of cholinesterase associated with Alzheimer's disease pathology.
Difluoromethyl ketones: Potent inhibitors of wild type and carbamate-insensitive G119S mutant Anopheles gambiae acetylcholinesterase
Camerino, Eugene,Wong, Dawn M.,Tong, Fan,K?rber, Florian,Gross, Aaron D.,Islam, Rafique,Viayna, Elisabet,Mutunga, James M.,Li, Jianyong,Totrov, Maxim M.,Bloomquist, Jeffrey R.,Carlier, Paul R.
, p. 4405 - 4411 (2015/10/12)
Malaria is a devastating disease in sub-Saharan Africa, and current vector control measures are threatened by emerging resistance mechanisms. With the goal of developing new, selective, resistance-breaking insecticides we explored α-fluorinated methyl ketones as reversible covalent inhibitors of Anopheles gambiae acetylcholinesterase (AgAChE). Trifluoromethyl ketones 5 demonstrated remarkable volatility in microtiter plate assays, but 5c,e-h exhibited potent (1-100 nM) inhibition of wild type (WT) AgAChE and weak inhibition of resistant mutant G119S mutant AgAChE. Fluoromethyl ketones 10c-i exhibited submicromolar to micromolar inhibition of WT AgAChE, but again only weakly inhibited G119S AgAChE. Interestingly, difluoromethyl ketone inhibitors 9c and 9g had single digit nanomolar inhibition of WT AgAChE, and 9g had excellent potency against G119S AgAChE. Approach to steady-state inhibition was quite slow, but after 23 h incubation an IC50 value of 25.1 ± 1.2 nM was measured. We attribute the slow, tight-binding G119S AgAChE inhibition of 9g to a balance of steric size and electrophilicity. However, toxicities of 5g, 9g, and 10g to adult A. gambiae in tarsal contact, fumigation, and injection assays were lower than expected based on WT AgAChE inhibition potency and volatility. Potential toxicity-limiting factors are discussed.
AROMATIC ACETYLCHOLINESTERASE INHIBITORS
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, (2008/06/13)
Compounds of general formula (I), stereosiomers and pharmaceutically acceptable salts thereof, wherein each of Z and Z' are independently H or F; Q is (a), CH(OH), (b); X is H, Br, Cl, F or CF3 ; Y is H, Br, Cl, F, OH, OR5, OC(O)R4, N3, CN, NO2, SO3 H, CO
