Tetrahydrobenzothiophene Derivatives: Conformationally Restricted Inhibitors of Type II Dehydroquinase

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.