Design, synthesis, and antifungal evaluation of Prp8 Intein-targeting small molecule inhibitors against Cryptococcus neoformans.

Cryptococcus neoformans, classified as a critical priority pathogen among fungi, highlights the urgent need for safe and effective novel antifungal drugs. The unique intein self-splicing process of the Prp8 protein in pathogenic fungi makes the Prp8 intein an attractive antifungal target. Taking the Prp8 intein inhibitor 6G-318S as a lead compound, a series of 1,2,3-thiadiazole derivatives were designed and synthesized. Among these, compound B5 exhibited excellent in vitro antifungal activity against C. neoformans (MIC = 1.0 μg/mL) and C. gattii (MIC = 0.5 μg/mL). Notably, B5 exhibited a 57-fold increase in aqueous solubility relative to 6G-318S, along with exceptional in vivo antifungal efficacy and favorable safety in animal models. Collectively, these results highlight compound B5 as a promising candidate for the development of Prp8 intein-targeting inhibitors as novel antifungal agents.