Design, synthesis, and evaluation of novel oxyacanthine derivatives for anti-SARS-CoV-2 activity

  • Bioorg Med Chem Lett. 2024 Nov 15:113:129951. doi: 10.1016/j.bmcl.2024.129951.
Jie Lu  1 ,  Yan Cheng  2 ,  Yumin Zhang  3 ,  Yi Wang  4 ,  Bingqing Xia  2 ,  Leike Zhang  3 ,  Abdullajon Odilov  2 ,  Yang He  2 ,  Xiangrui Jiang  2 ,  Feipu Yang  5 ,  Jingshan Shen  2
Affiliations
  • 1. School of Pharmacy, Henan University, Kaifeng 475004, PR China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
  • 2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
  • 3. State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, PR China.
  • 4. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
  • 5. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China. Electronic address: [email protected].
PMID: 39251112 DOI: 10.1016/j.bmcl.2024.129951
Abstract

Here, we report the synthesis of a series of oxyacanthine derivatives and evaluation for their anti-SARS-CoV-2 activity in Vero E6 cells. In order to eliminate the potential metabolic activation caused by para-methylene phenol moiety in oxyacanthine, totally 29 derivatives were designed and synthesized, resulting in 23 compounds with antivirus IC50 below 5.00 μM and 9 compounds with antivirus IC50 below 1.00 μM. Among them, amides compound 4a and 4d exhibited potent anti-SARS-CoV-2 activity and the most favorable selectivity index (SI) in vitro with the SI values of 115 and 70, respectively. The pharmacokinetic properties of 4a and 4d were also assessed. Much more improved exposure in mice, longer half-life (T1/2), and increased oral bioavailability were observed for both compounds 4a and 4d compared with oxyacanthine.

Keywords
Bisbenzylisoquinoline alkaloid; Oxyacanthine derivatives; SARS-CoV-2.
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