Design and structural analysis of aromatic inhibitors of type II dehydroquinase from Mycobacterium tuberculosis.

Abstract

3-Dehydroquinase, the third enzyme in the shikimate pathway, is a potential target for drugs against tuberculosis. Whilst a number of potent inhibitors of the Mycobacterium tuberculosis enzyme based on a 3-dehydroquinate core have been identified, they generally show little or no in vivo activity, and were synthetically complex to prepare. This report describes studies to develop tractable and drug-like aromatic analogues of the most potent inhibitors. A range of carbon-carbon linked biaryl analogues were prepared to investigate the effect of hydrogen bond acceptor and donor patterns on inhibition. These exhibited inhibitory activity in the high-micromolar range. The addition of flexible linkers in the compounds led to the identification of more potent 3-nitrobenzylgallate- and 5-aminoisophthalate-based analogues.

• Authors: Nigel I Howard, Marcio V B Dias, Fabienne Peyrot, Liuhong Chen, Marco F Schmidt, Tom L Blundell, Chris Abell
• Journal: ChemMedChem (ChemMedChem) Vol. 10 Issue 1 Pg. 116-33 (Jan 2015) ISSN: 1860-7187 [Electronic] Germany
• PMID: 25234229 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Bacterial Proteins
• Enzyme Inhibitors
• Isonicotinic Acids
• Shikimic Acid
• Hydro-Lyases
• 3-dehydroquinate dehydratase
• citrazinic acid

Topics

• Bacterial Proteins (antagonists & inhibitors, metabolism)
• Binding Sites
• Catalytic Domain
• Crystallography, X-Ray
• Drug Design
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Hydro-Lyases (antagonists & inhibitors, metabolism)
• Isonicotinic Acids (chemical synthesis, chemistry, pharmacology)
• Molecular Dynamics Simulation
• Mycobacterium tuberculosis (drug effects, enzymology)
• Shikimic Acid (chemistry)
• Structure-Activity Relationship