2. Academic Validation
  3. Discovery of Novel 7-Hydroxy-5-oxo-4,5-dihydrothieno[3,2- b]pyridine-6-carboxamide Derivatives with Potent and Selective Antifungal Activity against Cryptococcus Species

Discovery of Novel 7-Hydroxy-5-oxo-4,5-dihydrothieno[3,2- b]pyridine-6-carboxamide Derivatives with Potent and Selective Antifungal Activity against Cryptococcus Species

  • J Med Chem. 2022 Aug 25;65(16):11257-11269. doi: 10.1021/acs.jmedchem.2c00794.
Liping Li 1,  Hao Wu 1,  Shuo Zhu 1,  Zhe Ji 1,  Xiaochen Chi 2 3,  Fei Xie 2,  Yumeng Hao 2,  Hui Lu 1,  Feng Yang 1,  Lan Yan 4,  Dazhi Zhang 1 2,  Yuanying Jiang 1,  Tingjunhong Ni 1
Affiliations

Affiliations

  • 1 Department of Pharmacy, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, No. 1239 Siping Road, Shanghai 200092, China.
  • 2 Department of Organic Chemistry, School of Pharmacy, Navy Medical University, PLA, No. 325 Guohe Road, Shanghai 200433, China.
  • 3 School of Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 4 Center for New Drug Research, School of Pharmacy, Navy Medical University, PLA, No. 325 Guohe Road, Shanghai 200433, China.
PMID: 35922963 DOI: 10.1021/acs.jmedchem.2c00794
Abstract

Cryptococcus neoformans and Cryptococcus gattii can cause fatal invasive infections, especially in immunocompromised patients. However, few Antifungal drugs are available to help treat cryptococcosis. In this study, by compound library screening, we presented the first report of hit compound P163-0892, which had potent in vitro and in vivo Antifungal activity against Cryptococcus spp. In vitro tests showed that P163-0892 was not cytotoxic and had highly selective and strong Antifungal activities against Cryptococcus spp. with MIC values less than 1 μg/mL. Synergism of P163-0892 and fluconazole was also observed in vitro. The in vivo Antifungal efficacy of P163-0892 was assessed in a wax moth larval fungal Infection model, and treatment with 10 mg/kg P163-0892 caused a significant reduction in Fungal burden and significant extension of the survival time. Taken together, our data indicate that the hit compound P163-0892 warrants further investigation as a novel anti-Cryptococcus agent.

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