Structure-based design and synthesis of C-1- and C-4-modified analogs of zanamivir as neuraminidase inhibitors.

In order to exploit the 430-cavity in the active sites of neuraminidases, 22 zanamivir analogs with C-1 and C-4 modification were synthesized, and their inhibitory activities against both group-1 (H5N1, H1N1) and group-2 neuraminidases (H3N2) were determined. Compound 9f exerts the most potency, with IC(50) value of 0.013, 0.001, and 0.09 μM against H3N2, H5N1, and H1N1, which is similar to that of zanamivir (H3N2 IC(50) = 0.0014 μM, H5N1 IC(50) = 0.012 μM, H1N1 IC(50) = 0.001 μM). Pharmacokinetic studies of compound 9f in rats showed a much longer plasma half-life (t(1/2)) than that of zanamivir following administration (po dose). Molecular modeling provided information about the binding model between the new inhibitors and neuraminidase, with the elongated groups at the C-1-position being projected toward the 430-loop region. This study may represent a novel starting point for the future development of improved antiflu agents.

[1]  Gavin J. Williams,et al.  Creation of a tailored aldolase for the parallel synthesis of sialic acid mimetics. , 2005, Angewandte Chemie.

[2]  Andy M Mason,et al.  Highly potent and long-acting trimeric and tetrameric inhibitors of influenza virus neuraminidase. , 2004, Bioorganic & medicinal chemistry letters.

[3]  P. Kerry,et al.  Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase , 2010, Nature communications.

[4]  P. Colman,et al.  Three‐dimensional structure of the complex of 4‐guanidino‐Neu5Ac2en and influenza virus neuraminidase , 1995, Protein science : a publication of the Protein Society.

[5]  Hong Liu,et al.  QSAR analyses on avian influenza virus neuraminidase inhibitors using CoMFA, CoMSIA, and HQSAR , 2006, J. Comput. Aided Mol. Des..

[6]  Zhuo-rong Li,et al.  Synthesis and anti-influenza activities of carboxyl alkoxyalkyl esters of 4-guanidino-Neu5Ac2en (zanamivir). , 2007, Bioorganic & medicinal chemistry letters.

[7]  R. Sidwell,et al.  Oral Administration of a Prodrug of the Influenza Virus Neuraminidase Inhibitor GS 4071 Protects Mice and Ferrets against Influenza Infection , 1998, Antimicrobial Agents and Chemotherapy.

[8]  Jung-Hsin Lin,et al.  Remarkable loop flexibility in avian influenza N1 and its implications for antiviral drug design. , 2007, Journal of the American Chemical Society.

[9]  Takeshi Masuda,et al.  Synthesis and anti-influenza evaluation of orally active bicyclic ether derivatives related to zanamivir. , 2003, Bioorganic & medicinal chemistry letters.

[10]  Gavin J. Williams,et al.  Synthesis of screening substrates for the directed evolution of sialic acid aldolase: towards tailored enzymes for the preparation of influenza A sialidase inhibitor analogues. , 2005, Organic & biomolecular chemistry.

[11]  P. Wyatt,et al.  Approaches to carbocyclic analogues of the potent neuraminidase inhibitor 4-guanidino-Neu5Ac2en. X-Ray molecular structure of N-[(1S,2S,6R)-2-azido-6-benzyloxymethyl-4-formylcyclohex-3-enyl]acetamide , 1995 .

[12]  Ali Dehghani,et al.  Syntheses and neuraminidase inhibitory activity of multisubstituted cyclopentane amide derivatives. , 2004, Journal of medicinal chemistry.

[13]  A. Yang,et al.  A practical synthesis of zanamivir phosphonate congeners with potent anti-influenza activity. , 2011, Journal of the American Chemical Society.

[14]  Yoshiyuki Kobayashi,et al.  Synthesis and anti-influenza virus activity of 4-guanidino-7-substituted Neu5Ac2en derivatives. , 2002, Bioorganic & medicinal chemistry letters.

[15]  J. C. Dyason,et al.  A study of the active site of influenza virus sialidase: an approach to the rational design of novel anti-influenza drugs. , 1996, Journal of medicinal chemistry.

[16]  Jianhua He,et al.  The 2009 pandemic H1N1 neuraminidase N1 lacks the 150-cavity in its active site , 2010, Nature Structural &Molecular Biology.

[17]  A. Yang,et al.  Analogs of zanamivir with modified C4-substituents as the inhibitors against the group-1 neuraminidases of influenza viruses. , 2010, Bioorganic & medicinal chemistry.

[18]  P. Colman.  New antivirals and drug resistance. , 2009, Annual review of biochemistry.

[19]  Jie Zhang,et al.  Recent advances in anti-influenza agents with neuraminidase as target. , 2006, Mini reviews in medicinal chemistry.

[20]  Satoru Kaneko,et al.  Synthesis and anti-influenza virus activity of 7-O-alkylated derivatives related to zanamivir. , 2002, Bioorganic & medicinal chemistry letters.

[21]  D. M. Ryan,et al.  4-Guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid is a highly effective inhibitor both of the sialidase (neuraminidase) and of growth of a wide range of influenza A and B viruses in vitro , 1993, Antimicrobial Agents and Chemotherapy.

[22]  H5N1 Moves Into Africa, European Union, Deepening Global Crisis , 2006, Science.

[23]  Robert V. Swift,et al.  Mechanism of 150-cavity formation in influenza neuraminidase , 2011, Nature communications.

[24]  J. Rollinger,et al.  Antiviral potential and molecular insight into neuraminidase inhibiting diarylheptanoids from Alpinia katsumadai. , 2010, Journal of medicinal chemistry.

[25]  Norbert Bischofberger,et al.  Identification of GS 4104 as an Orally Bioavailable Prodrug of the Influenza Virus Neuraminidase Inhibitor GS 4071 , 1998, Antimicrobial Agents and Chemotherapy.

[26]  Steven J. M. Jones,et al.  A novel small-molecule inhibitor of the avian influenza H5N1 virus determined through computational screening against the neuraminidase. , 2009, Journal of medicinal chemistry.

[27]  M. Yamashita,et al.  Synthesis and anti-influenza evaluation of polyvalent sialidase inhibitors bearing 4-guanidino-Neu5Ac2en derivatives. , 2002, Bioorganic & medicinal chemistry letters.

[28]  Weiliang Zhu,et al.  Syntheses of triazole-modified zanamivir analogues via click chemistry and anti-AIV activities. , 2006, Bioorganic & medicinal chemistry letters.

[29]  A J Elliott,et al.  BCX-1812 (RWJ-270201): discovery of a novel, highly potent, orally active, and selective influenza neuraminidase inhibitor through structure-based drug design. , 2000, Journal of medicinal chemistry.

[30]  Jonathan Greer,et al.  Influenza neuraminidase inhibitors: structure-based design of a novel inhibitor series. , 2003, Biochemistry.

[31]  P. Ramamoorthy,et al.  Solution Phase Synthesis of Amide-Linked N-Acetyl Neuraminic Acid, α-Amino Acid, and Sugar Amino Acid Conjugates1 , 1997 .

[32]  Vincent S Stoll,et al.  Structure-based characterization and optimization of novel hydrophobic binding interactions in a series of pyrrolidine influenza neuraminidase inhibitors. , 2005, Journal of medicinal chemistry.

[33]  F. Soriano,et al.  In-vitro antimicrobial activity of HMR 3004 (RU 64004) against erythromycin A-sensitive and -resistant Corynebacterium spp. isolated from clinical specimens. , 1998, The Journal of antimicrobial chemotherapy.

[34]  G. Air,et al.  Pyrrolidinobenzoic acid inhibitors of influenza virus neuraminidase: modifications of essential pyrrolidinone ring substituents. , 2003, Bioorganic & medicinal chemistry.

[35]  A J Elliott,et al.  Systematic structure-based design and stereoselective synthesis of novel multisubstituted cyclopentane derivatives with potent antiinfluenza activity. , 2001, Journal of medicinal chemistry.

[36]  M. Yamashita,et al.  Synthesis and in vivo influenza virus-inhibitory effect of ester prodrug of 4-guanidino-7-O-methyl-Neu5Ac2en. , 2009, Bioorganic & medicinal chemistry letters.

[37]  Stephanie Hamilton,et al.  Dimeric zanamivir conjugates with various linking groups are potent, long-lasting inhibitors of influenza neuraminidase including H5N1 avian influenza. , 2005, Journal of medicinal chemistry.

[38]  J. Rollinger,et al.  Influenza neuraminidase: a druggable target for natural products. , 2012, Natural product reports.

[39]  D. M. Ryan,et al.  Rational design of potent sialidase-based inhibitors of influenza virus replication , 1993, Nature.

[40]  J. Andrew McCammon,et al.  Characterizing Loop Dynamics and Ligand Recognition in Human- and Avian-Type Influenza Neuraminidases via Generalized Born Molecular Dynamics and End-Point Free Energy Calculations , 2009, Journal of the American Chemical Society.

[41]  Konrad Feichtinger,et al.  Diprotected Triflylguanidines: A New Class of Guanidinylation Reagents , 1998 .