title: Discovery of Novel Pyrazole Derivatives as Potent Neuraminidase Inhibitors against Influenza H1N1 Virus.
abstract: Ten pyrazole derivatives were synthesized and evaluated for their ability to inhibit the replication of influenza virions. All the compounds were synthesized in good-to-excellent yield, and the structures were ascertained with the help of (1) H NMR, (13) C NMR, mass, and elemental analysis. Among the tested series, compound 4i was identified as the most potent analog against the H1N1 virus, with IC50  = 5.4 µM, while the rest of the compounds showed mild-to-moderate inhibition of infection. Moreover, these compounds showed excellent inhibitory activity against influenza A neuraminidase (NA), with IC50 values ranging from 2.15 to 7.54 µM, among which compound 4i showed the most prominent inhibition with IC50  = 1.32 µM. To further exemplify the molecular contacts with NA, a molecular docking study of 4i was conducted with the 3D crystal structure of enzyme H5N1-NA in complex. Results showed that target molecules interact in a similar fashion with oseltamivir and zanamivir by creating interatomic contacts with Trp178, Glu227, and Arg371. Moreover, in the toxicity assay with the porcine renal proximal cell line, LLC-PK1, the confocal images showed no appreciable change in morphological character at the highest tested dose.
authors.affiliation: Department of Examination, Yidu Central Hospital of Weifang, Qingzhou City, Shandong, China.
authors.forename: Fan-Jie
authors.initials: FJ
authors.lastname: Meng
authors.affiliation: Department of Examination, Qianfoshan Hospital, Qingzhou City, Shandong, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.affiliation: Department of Anesthesiology, Yidu Central Hospital of Weifang, Qingzhou City, Shandong, China.
authors.forename: Wen-Zhen
authors.initials: WZ
authors.lastname: Dong
authors.affiliation: Department of Examination, Yidu Central Hospital of Weifang, Qingzhou City, Shandong, China.
authors.forename: Ming-Hong
authors.initials: MH
authors.lastname: Li
authors.affiliation: Department of Examination, Yidu Central Hospital of Weifang, Qingzhou City, Shandong, China.
authors.forename: Zhong-Zhen
authors.initials: ZZ
authors.lastname: Tuo
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002384:Catalysis; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002563:Cerium; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000201:enzymology; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry*; D062105:Molecular Docking Simulation; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D007546:Isoquinolines; D011720:Pyrazoles; D002563:Cerium; D009439:Neuraminidase; C004653:ceric ammonium nitrate
keywords: Anti-influenza; Docking; Neuraminidase; Pyrazole; Toxicity