- Design, synthesis, and activity evaluation of novel N-benzyl deoxynojirimycin derivatives for use as α-glucosidase inhibitors
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To obtain α-glucosidase inhibitors with high activity, 19 NB-DNJDs (N-benzyldeoxynojirimycin derivatives) were designed and synthesized. The results indicated that the 19 NBDNJDs displayed different inhibitory activities towards α-glucosidase in vitro. Compound 18a (1- (4-hydroxy-3-methoxybenzyl)-2-(hydroxymethyl) piperidine-3,4,5-triol) showed the highest activity, with an IC50 value of 0.207 ± 0.11 mM, followed by 18b (1-(3-bromo-4-hydroxy-5- methoxybenzyl)-2-(hydroxymethyl) piperidine-3,4,5-triol, IC50: 0.276 ± 0.13 mM). Both IC50 values of 18a and 18b were significantly lower than that of acarbose (IC50: 0.353 ± 0.09 mM). According to the structure-activity analysis, substitution of the benzyl and bromine groups on the benzene ring decreased the inhibition activity, while methoxy and hydroxyl group substitution increased the activity, especially with the hydroxyl group substitution. Molecular docking results showed that three hydrogen bonds were formed between compound 18a and amino acids in the active site of α- glucosidase. Additionally, an arene-arene interaction was also modelled between the phenyl ring of compound 18a and Arg 315. The three hydrogen bonds and the arene-arene interaction resulted in a low binding energy (-5.8 kcal/mol) and gave 18a a higher inhibition activity. Consequently, compound 18a is a promising candidate as a new α-glucosidase inhibitor for the treatment of type II diabetes.
- Zeng, Fanxin,Yin, Zhongping,Chen, Jiguang,Nie, Xuliang,Lin, Ping,Lu, Tao,Wang, Meng,Peng, Dayong
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- Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitor Agents: Optimization of Diarylanilines with High Potency against Wild-Type and Rilpivirine-Resistant E138K Mutant Virus
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Three series (6, 13, and 14) of new diarylaniline (DAAN) analogues were designed, synthesized, and evaluated for anti-HIV potency, especially against the E138K viral strain with a major mutation conferring resistance to the new-generation non-nucleoside reverse transcriptase inhibitor drug rilpivirine (1b). Promising new compounds were then assessed for physicochemical and associated pharmaceutical properties, including aqueous solubility, log P value, and metabolic stability, as well as predicted lipophilic parameters of ligand efficiency, ligand lipophilic efficiency, and ligand efficiency-dependent lipophilicity indices, which are associated with ADME property profiles. Compounds 6a, 14c, and 14d showed high potency against the 1b-resistant E138K mutated viral strain as well as good balance between anti-HIV-1 activity and desirable druglike properties. From the perspective of optimizing future NNRTI compounds as clinical trial candidates, computational modeling results provided valuable information about how the R1 group might provide greater efficacy against the E138K mutant.
- Liu, Na,Wei, Lei,Huang, Li,Yu, Fei,Zheng, Weifan,Qin, Bingjie,Zhu, Dong-Qin,Morris-Natschke, Susan L.,Jiang, Shibo,Chen, Chin-Ho,Lee, Kuo-Hsiung,Xie, Lan
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p. 3689 - 3704
(2016/05/24)
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- The taming of capsaicin. Reversal of the vanilloid activity of N-acylvanillamines by aromatic iodination
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Aromatic iodination ortho to the phenolic hydroxyl reverts the activity of the ultrapotent vanilloid agonist resiniferatoxin (RTX, 1a), generating the ultrapotent antagonist 5′-iodoRTX (1b). To better understand the role of iodine in this remarkable switch of activity, a systematic investigation on the halogenation of vanillamides, a class of compounds structurally simpler than resiniferonoids, was carried out. The results showed that (a) the antagonistic activity depends on the site of halogenation and is maximal at C-6′, (b) iodine is more efficient than chlorine and bromine at reverting the agonistic activity, and (c) iodine-carbon exchange decreases antagonist activity. Iodine-induced reversal of vanilloid activity was also observed in vanillamides more powerful than capsaicin, but a poor correlation was found between agonistic and antagonistic potencies, suggesting that differences exist in the way vanillamides and their 6′-iodo derivatives bind to TRPV1.″
- Appendino, Giovanni,Daddario, Nives,Minassi, Alberto,Moriello, Aniello Schiano,De Petrocellis, Luciano,Di Marzo, Vincenzo
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p. 4663 - 4669
(2007/10/03)
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- Synthesis of the naphthalene portion of the rubromycins.
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[reaction: see text]. A synthesis of a reduced version of the naphthazarin found in the rubromycin class of natural products is reported. The naphthalene ring system is formed via a Doetz reaction with a symmetrical alkyne. Differentiation between the C1'
- Xie,Kozlowski
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p. 2661 - 2663
(2007/10/03)
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- Stereoselective Synthesis of the Dihydrobenzofuran Segments of the Ephedradine Alkaloids
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Syntheses of dihydrobenzofuran derivatives have involved formation of phenol substituted β-hydroxy esters by an aldol reaction followed by Lewis-acid-catalysed intramolecular cyclisation as key steps; the use of chiral oxazolidinones in the aldol reaction has formed the basis of enantiospecific syntheses.
- Baker, Raymond,Cooke, Nigel G.,Humphrey, Guy R.,Wright, Stanley H. B.,Hirshfield, Jordan
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p. 1102 - 1104
(2007/10/02)
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