Stereodivergent synthesis of piperidine iminosugars 1-deoxy-D-nojirimycin and 1-deoxy-D-altronojirimycin

Angelis, Martina De; Sappino, Carla; Mandic, Emanuela; D’Alessio, M. T.; Dominicis, M.G. De; Sannino, Sara; Primitivo, Ludovica; Mencarelli, Paolo; Ricelli, Alessandra; Righi, Giuliana

doi:10.1016/j.tet.2020.131837

Cited by 7 publications

(6 citation statements)

References 41 publications

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“…The HCl salts of 3 and 4 were also converted to the free bases, whose side chain conformations were determined in the same manner to be predominantly gg and gt , respectively (Figure S1). In parallel, intermediate 15 was treated with TFA to form diol 23 , which was debenzylated to afford 1‐deoxynojirimycin 2 [26] in 72 % yield.…”

Section: Figurementioning

confidence: 99%

Influence of Side Chain Conformation on the Activity of Glycosidase Inhibitors

et al. 2023

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Substrate side chain conformation impacts reactivity during glycosylation and glycoside hydrolysis and is restricted by many glycosidases and glycosyltransferases during catalysis. We show that the side chains of gluco and manno iminosugars can be restricted to predominant conformations by strategic installation of a methyl group. Glycosidase inhibition studies reveal that iminosugars with the gauche,gauche side chain conformations are 6-to 10-fold more potent than isosteric compounds with the gauche,trans conformation; a manno-configured iminosugar with the gauche,gauche conformation is a 27-fold better inhibitor than 1-deoxymannojirimycin. The results are discussed in terms of the energetic benefits of preorganization, particularly when in synergy with favorable hydrophobic interactions. The demonstration that inhibitor side chain preorganization can favorably impact glycosidase inhibition paves the way for improved inhibitor design through conformational preorganization.

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Section: Figurementioning

confidence: 99%

Influence of Side Chain Conformation on the Activity of Glycosidase Inhibitors

et al. 2023

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“…Hence, a new synthetic strategy was used relying on the versatile coupling of two building blocks (Scheme 2): the isothiocyanate derivatives 15a,n,o,v and the benzene-1,2-diamines 17a− m,q−u followed by intramolecular cyclization mediated by N,N′-diisopropylcarbodiimide (DIC) to provide the desired products 15 6a−v after removal of the silyl protecting group. 16 Isothiocyanate derivatives (15a, 15n, 15o, and 15v) were synthesized starting from reacting epoxides (9, 13n, 13o, and 13v) with sodium azide to afford (14a, 14n, 14o, and 14v), 17 which were subsequently protected with tert-butyldimethylsilyl chloride (TBDMS) 18 and then reduced using the Staudinger procedure to the corresponding amines 19 which upon reaction with di(1H-imidazol-1-yl)methanethione provided the desired isothiocyanates. 20 In parallel, benzene-1,2-diamines 17a−m,q− u were prepared from substitution of 1-fluoro-2-nitrobenzene derivatives 16a−d with various primary amines followed by reduction of the nitro group using zinc and ammonium chloride.. 21 Finally, compound 18 was prepared from 6f by a Mitsunobu reaction as outlined in Scheme 3.…”

Section: ■ Resultsmentioning

confidence: 99%

Design, Synthesis, and Evaluation of New 1H-Benzo[d]imidazole Based PqsR Inhibitors as Adjuvant Therapy for Pseudomonas aeruginosa Infections

Soukarieh,

Mashabi,

Richardson

et al. 2024

J. Med. Chem.

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Pseudomonas aeruginosa is one of the top priority pathogens that requires immediate attention according to the World Health Organisation (WHO). Due to the alarming shortage of novel antimicrobials, targeting quorum sensing (QS), a bacterial cell to cell signaling system controlling virulence, has emerged as a promising approach as an antibiotic adjuvant therapy. Interference with the pqs system, one of three QS systems in P. aeruginosa, results in reduction of bacterial virulence gene expression and biofilm maturation. Herein, we report a hit to lead process to finetune the potency of our previously reported inhibitor 1 (IC 50 3.2 μM in P. aeruginosa PAO1-L), which led to the discovery of 2- (4-(3-((6-chloro-1-isopropyl-1H-benzo[d]imidazol-2-yl)amino)-2-hydroxypropoxy)phenyl)acetonitrile (6f) as a potent PqsR antagonist. Compound 6f inhibited the PqsR-controlled P pqsA -lux transcriptional reporter fusion in P. aeruginosa at low submicromolar concentrations. Moreover, 6f showed improved efficacy against P. aeruginosa CF isolates with significant inhibition of pyocyanin, 2alkyl-4(1H)-quinolones production.

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“…(+)-1-Deoxynojirimycin (2), 7 (+)-1-deoxygalactonojirimycin (3), 9 (−)-1-deoxygulonojirimycin (4), 9 and (−)-1-deoxymannojirimycin (5). 11 (+)-1-Deoxynojirimycin ((+)-DNJ, 2), 65,84,102,103 (+)-1-deoxygalactonojirimycin ((+)-galacto-DNJ,…”

Section: Total Synthesismentioning

confidence: 99%

“…The resulting allylic alcohol (101) was protected using a MOM group. Ozonolysis of the terminal olefin in 102, followed by N-Cbz deprotection and reductive annulation using Pd(OH) 2 /H 2 , afforded pyrrolizidine (103). Universal deprotection of 103 under acidic conditions gave 16•HCl, which was neutralized to give (+)-casuarine ( 16).…”

Section: Reviewmentioning

confidence: 99%