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Animal / preclinicalJournal of medicinal chemistry · 2026

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

Keren Xu, Zekai Cui, Yingjia Ding … Zhikun Yang

GastroenterologyAnimal / preclinical

New thiadiazole compound 3-5B potently blocks gut bacterial β-glucuronidase in the laboratory

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

Keren Xu et al. · Journal of medicinal chemistry · 2026

Background

Gut microbial β-glucuronidase has attracted attention as a potential therapeutic target for mitigating irinotecan (CPT-11)-induced late-onset diarrhea and intestinal injury.

IC50 = 0.39 μM

Results

Only 0.39 μM blocks half the E. coli enzyme's activity; lower means more potent

n = 60 thioester derivatives

More results

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).

More results

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.

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Conclusion

Collectively, these findings identify 3-5B as a promising lead scaffold for the development of EcGUS inhibitors.

Post

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

New thiadiazole compound 3-5B potently blocks gut bacterial β-glucuronidase in the laboratory

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