Design, Synthesis, Biological Evaluation and In Silico Studies of Pyrazole-Based NH2-Acyl Oseltamivir Analogues as Potent Neuraminidase Inhibitors

被引：9

作者：

Ye, Jiqing ^{[1
]}

Lin, Lin ^{[2
]}

Xu, Jinyi ^{[3
,4
]}

Chan, Paul Kay-sheung ^{[2
,5
]}

Yang, Xiao ^{[2
]}

Ma, Cong ^{[1
]}

机构：

[1] Hong Kong Polytech Univ, Dept Appl Biol & Chem Technol, State Key Lab Chem Biol & Drug Discovery, Kowloon, Hong Kong, Peoples R China

[2] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Microbiol, Shatin, Hong Kong, Peoples R China

[3] China Pharmaceut Univ, State Key Lab Nat Med, 24 Tong Jia Xiang, Nanjing 210009, Peoples R China

[4] China Pharmaceut Univ, Dept Med Chem, 24 Tong Jia Xiang, Nanjing 210009, Peoples R China

[5] Chinese Univ Hong Kong, Stanley Ho Ctr Emerging Infect Dis, Shatin, Hong Kong, Peoples R China

来源：

PHARMACEUTICALS | 2021年 / 14卷 / 04期

关键词：

influenza virus; neuraminidase inhibitor; 150-cavity; oseltamivir derivatives; pyrazole;

D O I：

10.3390/ph14040371

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Oseltamivir represents one of the most successful neuraminidase (NA) inhibitors in the current anti-influenza therapy. The 150-cavity of NA was identified as an additional binding pocket, and novel NA inhibitors have been designed to occupy the 150-cavity based on the structure information of oseltamivir carboxylate (OC) in complex with NA. In this study, a series of C-5-NH2-acyl derivatives of OC containing the pyrazole moiety were synthesized. Several derivatives exhibited substantial inhibitory activity against NA. Moreover, in silico ADME evaluation indicated that the derivatives were drug-like with higher oral absorption rates and greater cell permeability than OC. Additionally, molecular docking studies revealed that the derivatives interacted with both the NA enzyme active site and 150-cavity as expected. The results provided useful information for further structural optimization of OC.

引用

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