Design and Structural Analysis of Aromatic Inhibitors of Type II Dehydroquinase from Mycobacterium tuberculosis |
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| Authors: | Dr Nigel I Howard Dr Marcio V B Dias Dr Fabienne Peyrot Dr Liuhong Chen Dr Marco F Schmidt Prof Tom L Blundell Prof Chris Abell |
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| Affiliation: | 1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW (UK);2. Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA (UK);3. Present address: Universidade de S?o Paulo, Departamento de Microbiologia, Av. Prof. Lineu Prestes, 1374 – Ed. Biomédicas II, Cidade Universitária, CEP 05508‐900, S?o Paulo (Brazil) |
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| 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. |
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| Keywords: | dehydroquinase drug design inhibitors Mycobacterium tuberculosis protein structures |
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