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Competitive inhibitors of Helicobacter pylori type II dehydroquinase: Synthesis, biological evaluation, and NMR studies

Lookup NU author(s): Dr Heather Lamb, Professor Alastair Hawkins


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Several 3-heteroaryl analogs of the known dehydroquinase inhibitor (1R,4R,5R)-1,4,5-trihydroxy-2-cyclohexene-1-carboxylic acid (4) were synthesized and tested as inhibitors of Helicobacter pylori type II dehydroquinase, the third enzyme of the shikimic acid pathway. All of these compounds proved to be reversible competitive inhibitiors of this enzyme and proved to be, with the exception of nitrile 8e, more potent than the parent inhibitor 4 (K-i= 370 mu M). The 2-thienyl derivative 8b was found to be the most potent inhibitor of the series and has a K-i value of 540 nm, which is almost seven hundred times lower than that of the parent inhibitor. The 3-nitrothienyl derivative 8d and 2-furanyl derivative 8a also had a good affinity of 1 mu m. The conformation of the potent competitive inhibitor 8b, when bound in the active site of the H. pylori enzyme, was elucidated by ID-selective inversion NOE, Saturation. Transfer Difference (STD) and transferred NOESY NMR experiments. One of the conformations that exists in solution for the potent competitive inhibitor 2-thienyl derivative 8b is selected when it is bound to the active site of the enzyme. In the bound conformation derivative 8b has the sulfur atom of its thienyl group oriented towards the double bond of the cyclohexene moiety. The large STD effects observed for the aromatic protons of 8b show that it is the thiophene side of the ligand that makes closest contact with enzyme protons. Docking studies using GOLD3.0.1 suggest that the conformation determined by NMR allows strong lipophilic interactions with the enzyme residues Pro9, Asn10, Hell, Gly78 and Ala79. Competitive STD experiments carried out with high-, medium- and low-affinity ligands 8b, 5d and 5f show that they all bind in the same site of Helicobacter pylori dehydroquinose.

Publication metadata

Author(s): Sanchez-Sixto C, Prazeres VFV, Castedo L, Suh SW, Lamb H, Hawkins AR, Canada FJ, Barbero JJ, Gonzalez-Bello C

Publication type: Article

Publication status: Published

Journal: ChemMedChem

Year: 2008

Volume: 3

Issue: 5

Pages: 756-770

ISSN (print): 1860-7179

ISSN (electronic): 1860-7187

Publisher: Wiley - V C H Verlag GmbH & Co. KGaA


DOI: 10.1002/cmdc.200700307


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