2. Academic Validation
  3. Discovery of DC20 as a potential non-nucleoside reverse transcriptase inhibitor with excellent pharmacokinetic properties

Discovery of DC20 as a potential non-nucleoside reverse transcriptase inhibitor with excellent pharmacokinetic properties

  • Bioorg Med Chem Lett. 2025 May 13:125-126:130267. doi: 10.1016/j.bmcl.2025.130267.
Jia-Yu Liu 1,  Meng-Di Ma 2,  Yi-Ming Li 1,  Cong-Qiang Xie 1,  Jia-Rui Wu 1,  Kai-Ting Yan 1,  Deng-Yu Niu 1,  Rong-Hua Luo 3,  Yue-Ping Wang 1,  Yong-Tang Zheng 3,  Zhen-Nan She 4,  Hong-Bing Zhang 5,  Liu-Meng Yang 6,  Yan-Ping He 7
Affiliations

Affiliations

  • 1 Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Key Laboratory of Cross-Border Infectious Disease Control and Prevention and Novel Drug Development, Yunnan Provincial Center for Research & Development of Natural Products; School of Pharmacy, Yunnan University, Kunming 650500, China.
  • 2 State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
  • 4 School of Pharmaceutical Sciences, Kunming Medical University, Kunming 650500, China.
  • 5 Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Key Laboratory of Cross-Border Infectious Disease Control and Prevention and Novel Drug Development, Yunnan Provincial Center for Research & Development of Natural Products; School of Pharmacy, Yunnan University, Kunming 650500, China. Electronic address: zhanghb@ynu.edu.cn.
  • 6 State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China. Electronic address: lmyang@mail.kiz.ac.cn.
  • 7 Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Key Laboratory of Cross-Border Infectious Disease Control and Prevention and Novel Drug Development, Yunnan Provincial Center for Research & Development of Natural Products; School of Pharmacy, Yunnan University, Kunming 650500, China. Electronic address: yphe@ynu.edu.cn.
PMID: 40374151 DOI: 10.1016/j.bmcl.2025.130267
Abstract

S-DACOs are a series of non-nucleoside Reverse Transcriptase inhibitors (NNRTIs) known for their effective Antiviral activity and low cytotoxicity, although their water solubility and bioavailability have been suboptimal. In this study, we synthesized and evaluated 25 novel compounds, most of which demonstrated a CLogP below 5 and exhibited potent Antiviral activity against HIV-1IIIB with EC50 values ranging from 0.86 to 0.004 μmol/L. Among them, compound DC20 (EC50 = 0.004 μM, CC50 = 134.21 ± 0.78 μM, SI = 33,552) emerged as particularly promising, it effectively targets Reverse Transcriptase and maintains high efficacy against mutant strains V106M, K103N, and Y181C. Particularly notable is that DC20 possesses excellent pharmacokinetic properties, with an oral bioavailability reaching up to 89.1 %. Given its high potency and low toxicity, DC20 holds significant potential for drug development and may serve as a critical candidate for future clinical applications. Further investigations will focus on its pharmaceutical viability.

Keywords

Anti HIV-1 activity; Bioavailability; NNRTIs; Reverse transcriptase; S-DACOs.

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