Rational Design, Synthesis, and Evaluation of Nanomolar Type II Dehydroquinase Inhibitors

Payne, Richard J.; Peyrot, Fabienne; Kerbarh, Olivier; Abell, Andrew D.; Abell, Chris

doi:10.1002/cmdc.200700032

Cited by 30 publications

(32 citation statements)

References 30 publications

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“…Specifically, the 3-substituted cyclohexene derivatives 31-36, the tetrahydrobenzothiophene derivatives 37, the O-alkyl derivatives 38, and the 2,3-disubstituted compounds 39 were reported ( Fig. 9) [54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71]. A summary of the inhibition constants of these compounds against Mt-DHQ2 and Hp-DHQ2 are shown in Tables 1 and 2.…”

Section: Enolate Intermediate Mimeticsmentioning

confidence: 99%

Inhibition of Shikimate Kinase and Type II Dehydroquinase for Antibiotic Discovery: Structure-Based Design and Simulation Studies

González‐Bello

2015

CTMC

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Abstract:The loss of effectiveness of current antibiotics caused by the development of drug resistance has become a severe threat to public health. Current widely used antibiotics are surprisingly targeted at a few bacterial functions -cell wall, DNA, RNA, and protein biosynthesis -and resistance to them is widespread and well identified. There is therefore great interest in the discovery of novel drugs and therapies to tackle antimicrobial resistance, in particular drugs that target other essential processes for bacterial survival. In the past few years a great deal of effort has been focused on the discovery of new inhibitors of the enzymes involved in the biosynthesis of aromatic amino acids, also known as the shikimic acid pathway, in which chorismic acid is synthesized. The latter compound is the synthetic precursor of L-Phe, L-Tyr, L-Phe, and other important aromatic metabolites. These enzymes are recognized as attractive targets for the development of new antibacterial agents because they are essential in important pathogenic bacteria, such as Mycobacterium tuberculosis and Helicobacter pylori, but do not have any counterpart in human cells. This review is focused on two key enzymes of this pathway, shikimate kinase and type II dehydroquinase. An overview of the use of structure-based design and computational studies for the discovery of selective inhibitors of these enzymes will be provided. A detailed view of the structural changes caused by these inhibitors in the catalytic arrangement of these enzymes, which are responsible for the inhibition of their activity, is described.

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Section: Enolate Intermediate Mimeticsmentioning

confidence: 99%

Inhibition of Shikimate Kinase and Type II Dehydroquinase for Antibiotic Discovery: Structure-Based Design and Simulation Studies

González‐Bello

2015

CTMC

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“…TLC was performed on silica gel 60/Kieselguhr F 254 . 1 H and 13 C NMR spectra were recorded on a Varian VXR300 (299. = 7.24, 13 C = 77.0).…”

Section: General Techniquesmentioning

confidence: 99%

“…= 7.24, 13 C = 77.0). Carbon assignments are based on 13 C and APT 13 C experiments. Splitting patterns are indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).…”

Section: General Techniquesmentioning

confidence: 99%

A novel catalytic asymmetric route towards skipped dienes with a methyl-substituted central stereogenic carbon

et al. 2013

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A novel catalytic asymmetric route towards skipped dienes with a methyl-substituted central stereogenic carbon Huang, Yange; Fañanás-Mastral, Martín; Minnaard, Adriaan J.; Feringa, Bernard IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2013Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Huang, Y., Fañanás-Mastral, M., Minnaard, A. J., & Feringa, B. (2013) 1, 132.8, 132.4, 131.6, 128.6, 128.1, 127.6, 126.4, 63.5.((1E,3E)-5-Bromopenta-1,3-dienyl)benzene (1a). To a stirred solution of NBS (4.17 g, 23.4 mmol, 1.3 eq) in DCM (40 mL) at -20 o C was added Me 2 S (0.98 g, 1.2 mL, 28.9 mmol, 1.83 eq) slowly over 5 min.The reaction mixture was stirred for 15 min before a solution of allylic alcohol 9 (2.5 g, 15.6 mmol) in 10 mL of DCM was added dropwise over 10 min. The mixture was quenched with a saturated aqueous NH 4 Cl solution (50 mL) when TLC showed full conversion and after the mixture was warmed up to room temperature, the layers were separated. The organic layer was washed with water (3 x 20 mL), dried over Na 2 SO 4 , filtered and concentrated to give crude 1a as a white solid (2.83 g, 81%) which was used in the next step (asymmetric allylic alkylation) immediately due to instability. Electronic Supplementary Material (ESI) for Chemical Communications This journal is

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“…94 We have identified water soluble QA amide 3 which possess potent anti-inflammatory activity. 118,119 QA amide lead 3 will serve as a new template for anti-inflammatory agents.…”

Section: 93mentioning

confidence: 99%

“…92,93 Payne designed derivatives to act as type II dehydroquinase inhibitors. 94 In 2001, Sefkow has synthesized CGA, 1-, 4-, and 5-Caffeoylquinic Acid as antioxidant. 95,96 Those esters have many other properties such as antibacterial, antimutagenic, antitumor, and antiviral.…”

Section: Synthesis Of Qa and Its Derivativesmentioning

confidence: 99%

Discovery of Quinic Acid Derivatives as Oral Anti-inflammatory Agents

Zeng¹

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Rational Design, Synthesis, and Evaluation of Nanomolar Type II Dehydroquinase Inhibitors

Cited by 30 publications

References 30 publications

Inhibition of Shikimate Kinase and Type II Dehydroquinase for Antibiotic Discovery: Structure-Based Design and Simulation Studies

Inhibition of Shikimate Kinase and Type II Dehydroquinase for Antibiotic Discovery: Structure-Based Design and Simulation Studies

A novel catalytic asymmetric route towards skipped dienes with a methyl-substituted central stereogenic carbon

Discovery of Quinic Acid Derivatives as Oral Anti-inflammatory Agents

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