Structure-based design, synthesis, and biological evaluation of inhibitors of Mycobacterium tuberculosis type II dehydroquinase

The syntheses by Suzuki cross-coupling of 12 5-aryl analogues of the known inhibitor (1R,3R,4R)-1,3,4-trihydroxycyclohex-5-en-1-carboxylic acid are reported. These compounds were found to be reversible competitive inhibitors against Mycobacterium tuberculosis type II dehydroquinase, the third enzyme of the shikimic acid pathway. The most potent inhibitor, the 3-nitrophenyl derivative, has a K(i) of 54 nM, over 180 times more potent than the reported inhibitor (1R,3R,4R)-5-fluoro-1,3,4-trihydroxycyclohex-5-en-1-carboxylic acid and more than 700 times lower than the K(M) of the substrate, making it the most potent known inhibitor against any type II dehydroquinase. Docking studies using GOLD (version 2.2) indicated a key electrostatic binding interaction between the aromatic rings and Arg19, a residue that has been identified as essential for enzyme activity.