Synthesis and biological evaluation of 12N-substituted tricyclic matrinic derivatives as a novel family of anti-influenza agents.

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 a 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 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.