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

ChemMedChem
Cristina Sánchez-SixtoConcepción González-Bello

Abstract

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 8 e, more potent than the parent inhibitor 4 (K(i)=370 microM). The 2-thienyl derivative 8 b 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 8 d and 2-furanyl derivative 8 a also had a good affinity of 1 microM. The conformation of the potent competitive inhibitor 8 b, when bound in the active site of the H. pylori enzyme, was elucidated by 1D-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 8 b is selected when it is bound to the active site of the enzyme. In the bound conformation derivative 8 b has the sulfur atom of its thienyl gr...Continue Reading

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Citations

Jul 26, 2011·Journal of Medicinal Chemistry·Lorena TizónConcepción González-Bello
Apr 3, 2014·Journal of Medicinal Chemistry·Beatriz BlancoConcepción González-Bello
Jul 18, 2014·Organic & Biomolecular Chemistry·Edward E KorshinMichael Bendikov
Mar 27, 2012·Organic & Biomolecular Chemistry·Beatriz BlancoConcepción González-Bello
Dec 4, 2012·ACS Chemical Biology·Emilio LenceConcepción González-Bello
Aug 21, 2013·Dalton Transactions : an International Journal of Inorganic Chemistry·Khuong Q VuongBarbara A Messerle
Oct 27, 2009·ChemMedChem·Verónica F V PrazeresConcepción González-Bello
Aug 5, 2016·Molecular Informatics·Mattia SturleseStefano Moro
Jan 8, 2014·The Biochemical Journal·Claire CoderchConcepción González-Bello
Jun 25, 2014·The Biochemical Journal·María ManeiroConcepción González-Bello
Jul 7, 2015·Journal of the American Chemical Society·Concepción González-BelloAlastair R Hawkins
May 25, 2016·Expert Opinion on Drug Discovery·Ki-Young Lee, Bong-Jin Lee
Mar 14, 2020·International Journal of Molecular Sciences·Sandra Salillas, Javier Sancho
Sep 9, 2009·Expert Review of Anti-infective Therapy·Megan J DuckworthGeorge L Mendz
May 26, 2018·Future Microbiology·Ayla Debraekeleer, Han Remaut
Jul 5, 2021·European Journal of Medicinal Chemistry·Elham GhobadiSaeed Emami

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