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Tetrahydrobenzothiophene Derivatives: Conformationally Restricted Inhibitors of Type II Dehydroquinase
Author(s) -
Paz Sonia,
Tizón Lorena,
Otero José M.,
LlamasSaiz Antonio L.,
Fox Gavin C.,
van Raaij Mark J.,
Lamb Heather,
Hawkins Alastair R.,
Lapthorn Adrian J.,
Castedo Luis,
GonzálezBello Concepción
Publication year - 2011
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.201000343
Subject(s) - stereochemistry , chemistry , catalysis , combinatorial chemistry , organic chemistry
Restriction is good for inhibition! Tetrahydrobenzothiophene‐derived rigid mimics of the type II dehydroquinase (DHQ2)‐catalyzed reaction intermediate are reported. These derivatives fix the interaction with the tyrosine, the base that initiates the enzymatic reaction, in an inappropriate orientation for catalysis. Two competitive inhibitors in the series, 2‐propenyl derivative 5 e and 2‐cyclopropylethyl compound 5 i (shown), were crystallized in complex with DHQ2 from Helicobacter pylori , and the X‐ray structures were determined at 1.95 Å and 1.85 Å, respectively.