Synthesis and Biological Evaluation of 12N-substituted Tricyclic Matrinic Derivatives as a Novel Family of Anti-Influenza Agents
| Autor: | Dan-Qing Song, Sheng Tang, Jin-Qiu Yin, Yu-Huan Li, Ying-Hong Li, Zhan-Dong Liu, Yan-Xiang Wang, Xin-Yue Cheng |
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| Rok vydání: | 2017 |
| Předmět: |
Drug
Male media_common.quotation_subject medicine.disease_cause 01 natural sciences Antiviral Agents Madin Darby Canine Kidney Cells Rats Sprague-Dawley Structure-Activity Relationship Alkaloids Dogs Influenza A Virus H1N1 Subtype Pharmacokinetics In vivo Drug Discovery Influenza A virus medicine Structure–activity relationship Animals IC50 media_common chemistry.chemical_classification 010405 organic chemistry Area under the curve Combinatorial chemistry 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry Quinolizines Tricyclic |
| Zdroj: | Medicinal chemistry (Shariqah (United Arab Emirates)). 14(8) |
| ISSN: | 1875-6638 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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