1198791-01-3Relevant articles and documents
A prodrug approach for improving antituberculosis activity of potent mycobacterium tuberculosis type II dehydroquinase inhibitors
Tizón, Lorena,Otero, José M.,Prazeres, Verónica F. V.,Llamas-Saiz, Antonio L.,Fox, Gavin C.,Van Raaij, Mark J.,Lamb, Heather,Hawkins, Alastair R.,Ainsa, José A.,Castedo, Luis,González-Bello, Concepción
experimental part, p. 6063 - 6084 (2011/10/09)
The synthesis of high-affinity reversible competitive inhibitors of Mycobacterium tuberculosis type II dehydroquinase, an essential enzyme in Mycobacterium tuberculosis bacteria, is reported. The inhibitors reported here are mimics of the enol intermediate and the effect of substitution on C2 was studied. The crystal structures of Mycobacterium tuberculosis type II dehydroquinase in complex with three of the reported inhibitors are also described. The results show that an aromatic substituent on C2 prevents the closure of the active site by impeding the hydrogen-bonding interaction of Arg108 with the essential Tyr24 of the flexible loop, the residue that initiates catalysis. Chemical modifications of the reported acids were also carried out to improve internalization into Mycobacterium tuberculosis through an ester prodrug approach. Propyl esters proved to be the most efficient in achieving optimal in vitro activities.
Synthesis and biological evaluation of new nanomolar competitive inhibitors of Helicobacter pylori type II dehydroquinase. Structural details of the role of the aromatic moieties with essential residues
Prazeres, Verónica F. V.,Tizón, Lorena,Otero, José M.,Guardado-Calvo, Pablo,Llamas-Saiz, Antonio L.,Van Raaij, Mark J.,Castedo, Luis,Lamb, Heather,Hawkins, Alastair R.,González-Bello, Concepción
experimental part, p. 191 - 200 (2010/05/19)
The shikimic acid pathway is essential to many pathogens but absent in mammals. Enzymes in its pathway are therefore appropriate targets for the development of novel antibiotics. Dehydroquinase is the third enzyme of the pathway, catalyzing the reversible dehydratation of 3-dehydroquinic acid to form 3-dehydroshikimic acid. Here we present the synthesis of novel inhibitors with high affinity for Helicobacter pylori type II dehydroquinase and efficient inhibition characteristics. The structure of Helicobacter pylori type II dehydroquinase in complex with the most potent inhibitor shows that the aromatic functional group interacts with the catalytic Tyr22 by π-stacking, expelling the Arg17 side chain, which is essential for catalysis, from the active site. The structure therefore explains the favorable properties of the inhibitor and will aid in design of improved antibiotics.
