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(7 H )‐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 n M . 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.