High‐Affinity Inhibitors of tRNA‐Guanine Transglycosylase Replacing the Function of a Structural Water Cluster

The tRNA‐modifying enzyme tRNA–guanine transglycosylase (TGT) is essential for the pathogenic mechanism of Shigella flexneri, the causing agent of the bacterial diarrheal disease shigellosis. Herein, the synthesis of a new class of rationally designed 6‐amino‐imidazo[4,5‐g]quinazolin‐8(7H)‐one‐ (lin‐benzoguanine) based inhibitors of TGT are reported. In order to accommodate a small hydrophobic crevice opening near the binding site of ribose‐34, 2‐aminoethyl substituents were introduced in position 4 of the heterocyclic scaffold. For this purpose, a synthetic sequence consisting of iodination, Suzuki cross‐coupling, hydroboration, Mitsunobu reaction, and Gabriel synthesis was employed, furnishing a primary amine that served as a common intermediate for the preparation of a series of derivatives. The resulting ligands displayed very low inhibition constants, down to K_i=2 nM . Substantial additional inhibitory potency is gained by interaction of terminal lipophilic groups attached to the substituent at position 4 with the hydrophobic crevice shaped by Val45 and Leu68. At the same time, the secondary ammonium center in the substituent displaces a cluster of water molecules, solvating the catalytic residues Asp102 and Asp280, without loss in binding affinity. In addition, a synthetic intermediate with an unusual 3,6,7,8,9,10‐hexahydroimidazo[4,5‐g][1,3]benzodiazepine core, as confirmed by X‐ray analysis, is reported.