Synthesis of polyhydroxylated piperidines and evaluation as glycosidase inhibitors (original) (raw)
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Chiron approaches to polyhydroxylated piperidines: promising glycosidase inhibitors
Arkivoc, 2002
New chiron approaches towards the syntheses of polyhydroxylated piperidine analogues are described. The methodologies involve 1,3-addition of methyl magnesium bromide and silyl ketene acetal to D-glucose derived nitrone, intramolecular Michael addition to D-glucose derived α,β-unsaturated ester and double reductive amination of 5-keto aldose as key steps.
2014
An efficient and practical strategy for the synthesis of (3R,4s,5S)-4-(2-hydroxyethyl) piperidine-3,4,5-triol and its N-alkyl derivatives 8a–f, starting from the D-glucose, is reported. The chiral pool methodology involves preparation of the C-3-allyl-a-D-ribofuranodialdose 10, which was converted to the C-5-amino derivative 11 by reductive amination. The presence of C-3-allyl group gives an easy access to the requisite hydroxyethyl substituted compound 13. Intramolecular reductive aminocyclization of C-5 amino group with C-1 aldehyde provided the c-hydroxyethyl substituted piperidine iminosugar 8a that was N-alkylated to get N-alkyl derivatives 8b–f. Iminosugars 8a–f were screened against glycosidase enzymes. Amongst synthetic N-alkylated iminosugars, 8b and 8c were found to be a-galactosidase inhibitors while 8d and 8e were selective and moderate a-mannosidase inhibitors. In addition, immunomodulatory activity of compounds 8a–f was examined. These results were substantiated by molecular docking studies using AUTODOCK 4.2 programme.
European journal of medicinal chemistry, 2018
Alzheimer's disease (AD) is the most common type of dementia and related to the degeneration of hippocampal cholinergic neurons, which dramatically affects cognitive ability. Acetylcholinesterase (AChE) inhibitors are employed as drugs for AD therapy. Three series of sulfonylhydrazone compounds were designed, and their ability to inhibit AChE was evaluated. Fifteen compounds were synthesized and twelve of them had IC 50 values of 0.64-51.09 mM. The preliminary structure-activity relationships indicated that the methylcatechol moiety and arylsulfonyl substituents generated better compounds than both the benzodioxole and alkylsulfonyl chains. Molecular dynamics studies of compound 6d showed that the interaction with the peripheral binding site of AChE was similar to donepezil, which may explain its low IC 50 (0.64 mM). Furthermore, the drug-likeness of 6d suggests that the compound may have appropriate oral absorption and brain penetration. Compound 6d also presented antiradical activity and was not cytotoxic to LL24 cells, suggesting that this compound might be considered safe. Our findings indicate that arylsulfonylhydrazones may be a promising scaffold for the design of new drug candidates for the treatment of AD.
The Journal of Organic Chemistry, 2012
The Jocic−Reeve and Corey−Link type reaction of dichloromethyllithium with suitably protected 5-ketohexofuranoses followed by treatment with sodium azide and sodium borohydride reduction gave 5-azido-5-hydroxylmethyl substituted hexofuranoses 7a−c with required geminal dihydroxymethyl group. Removal of protecting groups and converting the C-1 anomeric carbon into free hemiacetal followed by intramolecular reductive aminocyclization with in situ generated C5-amino functionality afforded corresponding 5C-dihydroxymethyl piperidine iminosugars 2a−c. Alternatively, removal of protecting groups in 7b and 7c and chopping of C1-anomeric carbon gave C2-aldehyde that on intramolecular reductive aminocyclization with C5-amino gave 4C-dihydroxymethyl pyrrolidine iminosugars 1b and 1c, respectively. On the basis of the 1 H NMR studies, the conformations of 2a/2b were assigned as 4 C 1 and that of 2c as 1 C 4 . The glycosidase inhibitory activities of all five iminosugars were studied with various glycosidase enzymes and compared with natural D-gluco-1-deoxynojirimycin (DNJ). All the five compounds were found to be potent inhibitors of rice α-glucosidase with K i and IC 50 values in the nanomolar concentration range. Iminosugars 2b and 1b were found to be more potent inhibitors than their parent iminosugar. These results were substantiated by in silico molecular docking studies. A dx.doi.org/10.1021/jo3009534 | J. Org. Chem. XXXX, XXX, XXX−XXX H 1a 2.92 (dd) 2.63 (dd) 2.90 (dd) J 1a,1e = 14.8 Hz J 1a,1e = 12.0 Hz J 1a,1e = 13.5 Hz J 1a,2e = 3.0 Hz J 1a,2a =12.0 Hz J 1a,2e = 4.1 Hz H 1e 3.01 (dd) 2.95 (dd) 2.98 (dd) J 1e,1a = 14.8 Hz J 1e,1a = 12.0 Hz J 1e,1a = 13.5 Hz J 1e,2e = 1.7 Hz J 1e,2a = 4.0 Hz J 1e,2e = 7.1 Hz . Conformations of 2a, 2b and 2c.
Some novel piperidine analogues having strong alpha glucosidase inhibition
Pakistan journal of pharmaceutical sciences, 2018
The idea of this study is based on the marvelous fact of nojirimycin and deoxy nojirimycin, naturally occurring from piperidine class and having their role as alpha glucosidase inhibitors. In the present work some hydroxyl piperidine analogues have been synthesized and analysed for their hypoglycemic effect through glucosidase inhibition owing to the structural resemblance with nojirimycin. The activity was done by spectral absorbance analysis using acarbose as standard. Two analogues (I & IV) were found to pose excellent activity having 87.4 and 54.7% inhibition respectively, hence strengthening the idea of studying piperidine analogiues as glucosidase inhibitors due to structural similarity with nojirimycin.
Tetrahedron, 2018
The fluorinated piperidine iminosugars 2a-4a and their N-octyl and N-decyl derivatives 2b,c-4b,c were synthesized from D-mannose/D-xylose using nucleophilic fluorination as the key step. The conformation of iminosugars 2/3, either 2 C 5 or 5 C 2 , was assigned based on the 1 H NMR studies at different pH. Immunomodulatory activity of 2a,c-4a,c was examined using Mixed Lymphocyte Reaction (MLR) and B-cell assay. The Nalkylated fluorinated D-manno-iminosugars 3b/4b were found to be better immunosuppressive agents (IC 50 = 5-6 µM) on T-cells. The fluorinated iminosugar 3a/4a act as potent and selective inhibitors of β-glucosidase (IC 50 = 4-8 µM). The N-alkyliminosugars 4b-c were found to be moderate inhibitors of α-glucosidase (yeast) and αgalactosidase (coffee beans), respectively.
Journal of the American Chemical Society, 2004
This article describes an efficient synthesis of a potent trehalase inhibitor, 1,1′-N-linked pseudodisaccharide 1 (consisting of two valienamines), in 14 steps with an overall yield of 12% and a first synthesis of 2 (consisting of two 2-epi-valienamines) in 15 steps with an overall yield of 24% from (-)quinic acid. The synthesis involves a stereospecific palladium-catalyzed coupling reaction between an allylic amine and an allylic chloride as the crucial step. The acetonide blocking groups were shown to be the best hydroxyl protecting groups, compatible with the palladium-catalyzed allylic amination reaction that afforded high yields of the 1,1′-N-linked pseudodisaccharides with a minimum amount of an elimination diene side product.
Tetrahedron-asymmetry, 2007
A series of chiral 1,4-morpholin-2,5-dione derivatives were synthesized starting from chiral synthons 1 and 2, monolactim ethers derived from L L-valine, and the absolute configurations of the new stereocentres were assigned. The substrates investigated behave as noncompetitive inhibitors against a-glucosidases and are inactive towards b-glucosidase, a-mannosidase and a-galactosidase. Three of these substrates show very good and specific inhibition abilities towards a-glucosidase.