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Competitive Inhibitors of Helicobacter pylori Type II Dehydroquinase: Synthesis, Biological Evaluation, and NMR Studies
Author(s) -
SánchezSixto Cristina,
Prazeres Verónica F. V.,
Castedo Luis,
Suh Se Won,
Lamb Heather,
Hawkins Alastair R.,
Cañada Francisco Javier,
JiménezBarbero Jesús,
GonzálezBello Concepción
Publication year - 2008
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200700307
Subject(s) - chemistry , stereochemistry , moiety , active site , thiophene , enzyme , derivative (finance) , cyclohexene , enzyme inhibitor , ligand (biochemistry) , nuclear magnetic resonance spectroscopy , non competitive inhibition , biochemistry , organic chemistry , receptor , financial economics , economics , catalysis
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 μ M ). 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 n M , 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 μ M . 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 group oriented towards the double bond of the cyclohexene moiety. The large STD effects observed for the aromatic protons of 8 b 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, Ile11, Gly78 and Ala 79. Competitive STD experiments carried out with high‐, medium‐ and low‐affinity ligands 8 b , 5 d and 5 f show that they all bind in the same site of Helicobacter pylori dehydroquinase.