Synthesis and Biological Evaluation of 12N-substituted Tricyclic Matrinic Derivatives as a Novel Family of Anti-Influenza Agents

Author(s): Sheng Tang, Yu-Huan Li, Xin-Yue Cheng, Jin-Qiu Yin, Ying-Hong Li, Dan-Qing Song, Yan-Xiang Wang*, Zhan-Dong Liu*.

Journal Name: Medicinal Chemistry

Volume 14 , Issue 8 , 2018

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Graphical Abstract:


Background: Influenza is still a serious threat to human health with significant morbidity and mortality, so it is desirable to develop novel anti-flu drug agents with novel structures.

Objective: The main purpose of this research was to explore broad-spectrum anti-flu agents and provide antiviral stockpiles in response to potential future influenza pandemics.

Methods: Fifteen novel 12N-substituted tricyclic matrinic derivatives were synthesized and evaluated for their anti-influenza activities against H1N1 subtype taking 12N-p-cyanobenzenesulfonyl matrinane (1) as the lead. All prepared compounds were characterized by 1H NMR, 13C NMR and ESI-HRMS. The pharmacokinetics (PK) profile of the key compound was also examined in this study.

Result: The structure-activity relationship study indicated that suitable benzyl groups on 12N atom might be beneficial for the activity. Among them, 12N-p-carboxybenzyl matrinic butane (17g) exhibited the most promising activity with an IC50 value of 16.2 µM and a selective index (SI) value of over 33.4. In addition, compound 17g displayed a good in vivo pharmacokinetic profile with an area under the curve (AUC0-∞) value of 9.89 µM·h.

Conclusion: We consider tricyclic matrinic butane derivatives to be a new class of anti-influenza agents and this study provided useful information on further optimization.

Keywords: Tricyclic matrinic derivatives, influenza A virus, H1N1 subtype, structure–activity relationship, drug-like, antivirus.

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Article Details

Year: 2018
Page: [764 - 772]
Pages: 9
DOI: 10.2174/1573406414666180222093033
Price: $58

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