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

  • Bioorg Chem. 2026 Mar:170:109490. doi: 10.1016/j.bioorg.2026.109490.
Ying Tao  1 ,  Lin Wang  1 ,  Xingsheng Huang  1 ,  Fang Wen  1 ,  Xiaoqin Tan  1 ,  Yiyun Zhu  1 ,  Jianhan Sun  2 ,  Xinyan Wan  3 ,  Xiuyun Tian  4 ,  Ting Guo  5 ,  Wei Zhou  6 ,  Guojian Liao  7
Affiliations
  • 1. College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China.
  • 2. College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China; National Demonstration Center for Experimental Pharmacy Education (Southwest University), Chongqing, China.
  • 3. College of Pharmaceutical Sciences, Chongqing Medical University, Chongqing 400715, China.
  • 4. State Key Laboratory of Microbial Diversity and Innovative Utilization, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
  • 5. College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China. Electronic address: [email protected].
  • 6. College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China. Electronic address: [email protected].
  • 7. College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China. Electronic address: [email protected].
PMID: 41539041 DOI: 10.1016/j.bioorg.2026.109490
Abstract

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.

Keywords
Antifungal; Cryptococcus neoformans; Prp8 intein; Structural optimization.
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