title: Design, synthesis, and in vitro biological evaluation of novel 6-methyl-7-substituted-7-deaza purine nucleoside analogs as anti-influenza A agents.
abstract: Among many subtypes of influenza A viruses, influenza A(H1N1) and A(H3N2) subtypes are currently circulating among humans (WHO report 2014-15). Therapeutically, the emergence of viral resistance to currently available drugs (adamantanes and neuraminidase inhibitors) has heightened alarms for developing novel drugs that could address diverse targets in the viral replication cycle in order to improve treatment outcomes. To this regard, the design and synthesis of nucleoside analog inhibitors as potential anti-influenza A agents is a very active field of research nowadays. In this study, we designed and synthesized a series of hitherto unknown 6-methyl-7-substituted-7-deaza purine nucleoside analogs, and evaluated for their biological activities against influenza A virus strains, H1N1 and H3N2. From the viral inhibition assay, we identified some effective compounds, among which, compounds 5x (IC50 = 5.88 μM and 6.95 μM for H1N1 and H3N2, respectively) and 5z (IC50 = 3.95 μM and 3.61 μM for H1N1 and H3N2, respectively) demonstrated potent anti-influenza A activity. On the basis of selectivity index, we conceive that compound 5x may serve as a chemical probe of interest for further lead optimization studies with a general aim of developing novel and effective anti-influenza A virus agents.
authors.affiliation: Guangzhou Institutes of Biomedicine and Heath, Chinese Academy of Sciences, 190 Kaiyuan Road, Guangzhou, 510530, PR China.
authors.forename: Cai
authors.initials: C
authors.lastname: Lin
authors.affiliation: Institute of Pharmaceutical Research, South China Normal University, Guangzhou, Guangdong, 510631, PR China.
authors.forename: Chenghai
authors.initials: C
authors.lastname: Sun
authors.affiliation: Institute of Pharmaceutical Research, South China Normal University, Guangzhou, Guangdong, 510631, PR China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Liu
authors.affiliation: Guangzhou Institutes of Biomedicine and Heath, Chinese Academy of Sciences, 190 Kaiyuan Road, Guangzhou, 510530, PR China.
authors.forename: Yiqian
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Guangzhou Institutes of Biomedicine and Heath, Chinese Academy of Sciences, 190 Kaiyuan Road, Guangzhou, 510530, PR China; University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing, 100049, PR China.
authors.forename: Muzammal
authors.initials: M
authors.lastname: Hussain
authors.affiliation: Guangzhou Institutes of Biomedicine and Heath, Chinese Academy of Sciences, 190 Kaiyuan Road, Guangzhou, 510530, PR China.
authors.forename: Junting
authors.initials: J
authors.lastname: Wan
authors.affiliation: Guangzhou Institutes of Biomedicine and Heath, Chinese Academy of Sciences, 190 Kaiyuan Road, Guangzhou, 510530, PR China.
authors.forename: Minke
authors.initials: M
authors.lastname: Li
authors.affiliation: Institute of Pharmaceutical Research, South China Normal University, Guangzhou, Guangdong, 510631, PR China.
authors.forename: Xue
authors.initials: X
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, PR China.
authors.forename: Ruiliang
authors.initials: R
authors.lastname: Jin
authors.affiliation: Guangzhou Institutes of Biomedicine and Heath, Chinese Academy of Sciences, 190 Kaiyuan Road, Guangzhou, 510530, PR China. Electronic address: tu_zhengchao@gibh.ac.cn.
authors.forename: Zhengchao
authors.initials: Z
authors.lastname: Tu
authors.affiliation: Guangzhou Institutes of Biomedicine and Heath, Chinese Academy of Sciences, 190 Kaiyuan Road, Guangzhou, 510530, PR China; State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, PR China. Electronic address: zhang_jiancun@gibh.ac.cn.
authors.forename: Jiancun
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000502:physiology; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects* / Q000502:physiology; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D053139:Oseltamivir / Q000494:pharmacology; D011684:Purine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012254:Ribavirin / Q000494:pharmacology; D053243:Zanamivir / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D011684:Purine Nucleosides; D053139:Oseltamivir; D012254:Ribavirin; D053243:Zanamivir
keywords: H1N1; H3N2; Influenza A; Nucleoside analogs