Design and synthesis of aromatic inhibitors of anthranilate synthase

Abstract

Aromatic analogues of chorismate were synthesised as potential inhibitors of anthranilate synthase. Molecular modelling using GOLD2.1 showed that these analogues docked into the active site of Serratia marcescens anthranilate synthase in the same conformation as chorismate. Most compounds were found to be micromolar inhibitors of S. marcescens anthranilate synthase. The most potent analogue, 3-(1-carboxy-ethoxy)-4-hydroxybenzoate (K_I 3 µM), included a lactyl ether side chain. This appears to be a good replacement for the enol-pyruvyl side chain of chorismate.