title: Design and synthesis of 1,2,3-triazole-containing N-acyl zanamivir analogs as potent neuraminidase inhibitors.
abstract: The design of potent metabolically stable neuraminidase (NA) inhibitors represents an attractive approach for treating influenza virus infection. In this study, we describe the exploitation of the 150-cavity in the active site of group 1 NA for the design, synthesis, and in vitro evaluation of new triazole-containing N-acyl derivatives related to Zanamivir. Inhibition studies with influenza virus NAs of group 1 (H1N1) and group 2 (H3N2) revealed that several of them are good inhibitors, with IC50 values in the low nanomolar (2.3 nM-31 nM) range. Substituents that form stable van der Waals interaction with the 150-cavity residues play crucial roles in NA inhibition as demonstrated by the potency of 6a (H1N1 IC50 = 2.3 nM, and H3N2 IC50 = 2.9 nM). Docking studies indicated that the cyclohexane-substituted triazole ring extended toward the hydrophobic region in the active site of group 1 NA in open form. The high potency observed for inhibitor 6a may be attributable to the highly favorable hydrophobic interactions in this region.
authors.affiliation: Department of Chemistry, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan.
authors.forename: Anindya
authors.initials: A
authors.lastname: Das
authors.affiliation: Department of Chemistry, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan.
authors.forename: Avijit K
authors.initials: AK
authors.lastname: Adak
authors.affiliation: Department of Chemistry, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan.
authors.forename: Kalyankumar
authors.initials: K
authors.lastname: Ponnapalli
authors.affiliation: Department of Chemistry, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan.
authors.forename: Chien-Hung
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Kai-Cheng
authors.initials: KC
authors.lastname: Hsu
authors.affiliation: Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu 30050, Taiwan.
authors.forename: Jinn-Moon
authors.initials: JM
authors.lastname: Yang
authors.affiliation: Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan 35053, Taiwan.
authors.forename: Tsu-An
authors.initials: TA
authors.lastname: Hsu
authors.affiliation: Department of Chemistry, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan. Electronic address: cclin66@mx.nthu.edu.tw.
authors.forename: Chun-Cheng
authors.initials: CC
authors.lastname: Lin
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D020134:Catalytic Domain; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000201:enzymology; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects / Q000201:enzymology; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014230:Triazoles / Q000737:chemistry*; D053243:Zanamivir / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D014230:Triazoles; D009439:Neuraminidase; D053243:Zanamivir
keywords: Influenza; Neuraminidase inhibitors; Triazole; Zanamivir