2. Academic Validation
  3. Design and synthesis of 7-membered lactam fused hydroxypyridinones as potent metal binding pharmacophores (MBPs) for inhibiting influenza virus PAN endonuclease

Design and synthesis of 7-membered lactam fused hydroxypyridinones as potent metal binding pharmacophores (MBPs) for inhibiting influenza virus PAN endonuclease

  • Eur J Med Chem. 2024 Jul 1:276:116639. doi: 10.1016/j.ejmech.2024.116639.
Lei Zhang 1,  Di Ke 2,  Yuting Li 3,  Hui Zhang 1,  Xi Zhang 4,  Sihan Wang 3,  Shaokai Ni 3,  Bo Peng 1,  Huixuan Zeng 3,  Tingjun Hou 1,  Yushen Du 3,  Peichen Pan 1,  Yongping Yu 5,  Wenteng Chen 6
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
  • 2 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, 230601, China.
  • 3 The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China.
  • 4 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China; Jinhua Institute of Zhejiang University, Jinhua, Zhejiang, 321299, China.
  • 5 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China; Jinhua Institute of Zhejiang University, Jinhua, Zhejiang, 321299, China; School of Pharmacy, Xinjiang Medical University, Urumqi, 830054, China.
  • 6 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China; Jinhua Institute of Zhejiang University, Jinhua, Zhejiang, 321299, China. Electronic address: wentengchen@zju.edu.cn.
PMID: 38964259 DOI: 10.1016/j.ejmech.2024.116639
Abstract

Since Influenza Virus RNA polymerase subunit PAN is a dinuclear Mn2+ dependent Endonuclease, metal-binding pharmacophores (MBPs) with Mn2+ coordination has been elucidated as a promising strategy to develop PAN inhibitors for influenza treatment. However, few attentions have been paid to the relationship between the optimal arrangement of the donor atoms in MBPs and anti-influenza A virus (IAV) efficacy. Given that, the privileged hydroxypyridinones fusing a seven-membered lactam ring with diverse side chains, chiral centers or cyclic systems were designed and synthesized. A structure-activity relationship study resulted in a hit compound 16l (IC50 = 2.868 ± 0.063 μM against IAV polymerase), the seven-membered lactam ring of which was fused a pyrrolidine ring. Further optimization of the hydrophobic binding groups on 16l afforded a lead compound (R, S)-16s, which exhibited a 64-fold more potent inhibitory activity (IC50 = 0.045 ± 0.002 μM) toward IAV polymerase. Moreover, (R, S)-16s demonstrated a potent anti-IAV efficacy (EC50 = 0.134 ± 0.093 μM) and weak cytotoxicity (CC50 = 15.35 μM), indicating the high selectivity of (R, S)-16s. Although the lead compound (R, S)-16s exhibited a little weaker activity than baloxavir, these findings illustrated the utility of a metal coordination-based strategy in generating novel MBPs with potent anti-influenza activity.

Keywords

Anti-Influenza; Hydroxypyridinone; Metal-binding pharmacophore; PA(N) endonuclease; RNA polymerase; Seven-membered lactam.

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