- Targeting Alzheimer's disease by investigating previously unexplored chemical space surrounding the cholinesterase inhibitor donepezil
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A series of twenty seven acetylcholinesterase inhibitors, as potential agents for the treatment of Alzheimer's disease, were designed and synthesised based upon previously unexplored chemical space surrounding the molecular skeleton of the drug donepezil, which is currently used for the management of mild to severe Alzheimer's disease. Two series of analogues were prepared, the first looking at the replacement of the piperidine ring in donepezil with different sized saturated N-containing ring systems and the second looking at the introduction of different linkers between the indanone and piperidine rings in donepezil. The most active analogue 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl 1-benzylpiperidine-4-carboxylate (67) afforded an in vitro IC50value of 0.03 ± 0.07 μM against acetylcholinesterase with no cytotoxicity observed (IC50of >100 μM, SH-SY5Y cell line). In comparison donepezil had an IC50of 0.05 ± 0.06 μM and an observed cytotoxicity IC50of 15.54 ± 1.12 μM. Molecular modelling showed a strong correlation between activity and in silico binding in the active site of acetylcholinesterase.
- van Greunen, Divan G.,Cordier, Werner,Nell, Margo,van der Westhuyzen, Chris,Steenkamp, Vanessa,Panayides, Jenny-Lee,Riley, Darren L.
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p. 671 - 690
(2017/02/10)
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- Synthesis of spirocyclopropyl γ-lactams by tandem intramolecular azetidine ring-opening/closing cascade reaction: Synthetic and mechanistic aspects
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The scope and limitations of a novel intramolecular azetidine ring-opening/closing cascade reaction affording spirocyclopropyl γ-lactams from azetidines in high regio- and stereoselectivity is reported. The key step of the process is a SN2-type ring-opening of TMSOTf-activated azetidine rings by silyl ketene acetals generated by treatment with TMSOTf and TEA. This study is a very rare example of nucleophilic ring-opening of azetidines that does not require formation of quaternary azetidinium salts by N-alkylation or the use of N-electron-withdrawing groups. Application of this process to 2-azetidinone system led to a complete change in reactivity and provide 6-aza-bicyclo[3.2.0]heptane derivatives via an unprecedented Mukaiyama aldol-like reaction involving an ester acceptor and a silyl imidate.
- Nocquet, Pierre-Antoine,Hazelard, Damien,Compain, Philippe
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experimental part
p. 4117 - 4128
(2012/07/28)
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- NHC-Catalyzed intramolecular redox amidation for the synthesis of functionalized lactams
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A very efficient NHC-catalyzed lactamization reaction is reported. For most cases, the ring expansion reaction proceeds to cleanly furnish five- and six-membered N-Ts and N-Bn lactams, without the need for further purification. Evidence is presented suggesting a dual role for the stoichiometric base: (1) deprotonation of the triazolium precatalyst and (2) activation of the nitrogen leaving group through hydrogen bonding.
- Thai, Karen,Wang, Li,Dudding, Travis,Bilodeau, Francois,Gravel, Michel
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supporting information; experimental part
p. 5708 - 5711
(2011/03/19)
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- Process
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There is provided a process for the production of a N-benzyl azetidine-2-carboxylic acid alkylphenyl, or alkyl, ester which process comprises the reaction of an optionally substituted alkylphenyl, or an optionally substituted alkyl, 2-bromo-4-chlorobutyrate with an optionally substituted benzylamine, which process may be used as part of an overall process for the production of azetidine-2-carboxylic acid.
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- Enzymatic resolution of methyl N-alkyl-azetidine-2-carboxylates by Candida antarctica lipase-mediated ammoniolysis
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A facile method for the synthesis of optically active azetidine-2- carboxylic acid derivatives is presented Racemic N-alkylated azetidine esters are resolved by lipase from Candida antarctica in an ammoniolysis reaction, and both the S-amide and the R-ester are obtained with excellent stereoselectivity.
- Starmans, Wim A. J.,Doppen, Roy G.,Thijs, Lambertus,Zwanenburg, Binne
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p. 429 - 435
(2007/10/03)
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- Photolytic reactions of chromium aminocarbene complexes. Conversion of amides to α-amino acids
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A variety of tertiary amides was converted to chromium aminocarbene complexes by reaction with Na2Cr(CO)5 and trimethylsilyl chloride. Photolysis of these carbene complexes in methanol or tert-butyl alcohol solvent produced α-amino esters in good to excellent yield. Aminocarbene complexes containing chiral oxazolidine groups were synthesized and photolyzed in alcohol to produce chiral α-amino esters in 50-93% de. Pentacarbonyl[(dibenzylamino)(methyl)carbene]chromium(0) was prepared in high yield by the N-benzylation of the corresponding monobenzyl amino complex. Base-assisted alkylation of the methyl group with a variety of halides followed by photolysis in methanol produced the alkylated alanine methyl ester in excellent overall yield. Other aminocarbene complexes underwent similar reactions. With chiral, optically active aminocarbene complexes, the alkylated alanine derivative was produced with high diastereoselectivity.
- Hegedus, Louis S.,Schwindt, Mark A.,De Lombaert, Stéphane,Imwinkelried, Rene
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p. 2264 - 2273
(2007/10/02)
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- TRANSFORMATION OF N-TOSYL-2-(1,3-BUTADIENYL)AZIRIDINE INTO N-TOSYL-2-ETHENYL-3-PYRROLINE.
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1,3-Butadienylaziridines or 1,3-butadienylazetidines activated by N-tosyl group smoothly rearrange to vinylpyrroline derivatives or vinylpiperidines in the presence of a catalytic amount of Pd(PPh3)4.Triphenyltin radical induced rearrangement of title compounds is also described.
- Fugami, Keigo,Miura, Katsukiyo,Morizawa, Yoshitomi,Oshima, Koichiro,Utimoto, Kiitiro,Nozaki, Hitosi
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p. 3089 - 3098
(2007/10/02)
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