Gut Bacterial β-Glucuronidase Blockade by 1,3,4-Thiadiazole-Containing Thioester Inhibitors Mitigates Irinotecan-Induced Gastrointestinal Toxicity.

Here, we designed and synthesized 60 thioester derivatives bearing a 1,3,4-thiadiazole moiety and evaluated their biological activities.

Kinetic studies showed that 3-5B acts as an uncompetitive EcGUS inhibitor ( K i = 0.60 μM).

Furthermore, molecular docking analysis suggested that 3-5B binds EcGUS with high affinity through interactions with residues Asp163, Glu413, and Trp549.

Notably, 3-5B showed no inhibitory effect on bovine liver β-glucuronidase, did not inhibit E. coli growth, and exhibited low cytotoxicity toward human Caco-2 cells.