Total synthesis of dryocrassin ABBA and its analogues with potential inhibitory activity against drug-resistant neuraminidases

• Published in: Bioorganic & medicinal chemistry Vol. 27; no. 17; pp. 3846 - 3852
• Main Authors: Hou, Bo, Liu, Ze, Yang, Xiao-Bei, Zhu, Wen-Fei, Li, Jin-Yu, Yang, Liu, Reng, Fu-Cai, Lv, Yong-Feng, Hu, Jiang-Miao, Liao, Guo-Yang, Zhou, Jun
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.09.2019; Elsevier
• Subjects: Anhui H7N9; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dryocrassin ABBA; Life Sciences & Biomedicine; Neuraminidase; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Shanghai H7N9; Total synthesis; Anhui H7N9; Shanghai H7N9; Dryocrassin ABBA; Total synthesis; Neuraminidase; PROTECTS MICE; DESIGN; VIRUS; INFLUENZA; DISCOVERY; OSELTAMIVIR; CHANNEL; DERIVATIVES
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2019.07.013

Total synthesis of dryocrassin ABBA and analogue structures with potential inhibitory activity against drug-resistant neuraminidases. [Display omitted] •Total synthesis of dryocrassin ABBA was achieved in nine steps with an over-all yield of 4.6%.•Dryocrassin ABBA and analogue structures have beneficial effects on treating avian influenza neuraminidases.•The AB cycle is high active against Anhui N9. The stems of Dryopteris crassirhizoma, one of the main components of Lianhua-Qingwen Formula (LQF) was traditionally used for heat-clearing and detoxifying. Dryocrassin ABBA is a key antiviral component in the herbal medicine while the compound is hard to get in large amounts with the features of homologous compounds, polyphenol groups, and low contents. Therefore, the present work aims to seek influenza H7N9 virus inhibitors from natural source by synthesis of dryocrassin ABBA and its analogues. As a result, total synthesis of the compound was achieved in nine steps with an over-all yield of 4.6%. Neuraminidases (NAs) inhibitory activities of the synthesized product and its analogues were evaluated afterward. Comparing with the positive control, OSV (9.6 μM), it was very exciting that dryocrassin ABBA and its analogues (b5 and e2) showed better NAs inhibitory activity against Anhui H7N9 with IC50 values of 3.6 μM, 2.5 μM and 1.6 μM. For the highly resistant Shanghai N9, these compounds can also show medium inhibitory activities. Docking results indicated the direct interaction of synthesized 3 hits with the key K294 by hydrogen bonds, but no direct interaction of OSV with the key K294 was observed in Shanghai N9. This study suggested that dryocrassin ABBA and its analogues especially AB, which consisted of polyphenol groups may have beneficial effects on treating avian influenza H7N9 virus.