Advertisement

Medicinal Chemistry Research

, Volume 26, Issue 5, pp 999–1009 | Cite as

Ethyl phosphoramidates of acyclovir: design, synthesis, molecular docking (HN Protein), and evaluation of antiviral and antioxidant activities

  • Subba Rao Devineni
  • Madhava Golla
  • Thaslim Basha Shaik
  • Janardhan Avilala
  • Madhu Sudhana Saddala
  • Narasimha Golla
  • Naga Raju ChamarthiEmail author
Original Research
  • 189 Downloads

Abstract

Synthesis of a series of new ethyl phosphoramidates 9aj of acyclovir through phosphorylation of hydroxy group followed by substitution of numerous amines/amino acid esters 7aj was accomplished. The structures of newly synthesized compounds were elucidated by spectroscopic data such as IR, NMR (1H, 13C, and 31P) and mass spectrophotometery, and elemental analyses. The synthesized products were screened for their antiviral activity against Newcastle disease virus, antioxidant potency by α, α-diphenyl-β-picrylhydrazyl free radical scavenging and nitric oxide radical scavenging methods, and antioxidant capacity by Ferric reducing antioxidant power method. The compound bearing 1-hydroxy 2-butylamine, 9c and amino acid ester derivatives, bonded with leucine methyl ester 9h and tyrosine methyl ester 9j were found to be potent inhibiters of Newcastle disease virus than that of acyclovir drug. The compounds, 9c (IC50 value, 22.5 ± 1.00 μg/mL), 9i (IC50 value, 21.5 ± 1.00 μg/mL) and 9j (IC50 value, 19.0 ± 1.50 μg/mL) were exhibited promising antioxidant activity while other compounds displayed moderate to good antioxidant activity. Docking study using molecular docking environment into haemaglutinin–neuraminidase protein has been carried out to find the potential selectivity and binding orientation of these new compounds into protein binding site. Interestingly, all the title compounds except 9a and 9g docked well into HN protein with considerable binding affinities better than that of acyclovir drug.

Keywords

Acyclovir Phosphoramidates Antiviral activity Antioxidant activity Molecular docking study Hemagglutinin neuraminidase protein 

Notes

Acknowledgements

The author (DSR) acknowledges University Grants Commission for providing Senior Research Fellowship under the program of Basic Scientific Research (BSR), and SKTB and GM are thankful to University Grants Commission for providing financial assistance. Also, we grateful to K. Naresh, Department of Biochemistry, S. V. University and Hyderabad Central University for contributing antioxidant activity and providing analytical data, respectively.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

44_2017_1819_MOESM1_ESM.doc (1.2 mb)
Supplementary Information

References

  1. Alexander DJ (2001) Gordon memorial lecture. Newcastle disease. Br Poult Sci 42:5–22CrossRefPubMedGoogle Scholar
  2. Anand BS, Hill JM, Dey S, Maruyama K, Bhattacharjee PS, Myles ME, Nashed YE, Mitra AK (2003) In vivo antiviral efficacy of a dipeptide acyclovir prodrug, val-val-acyclovir, against HSV-1 epithelial and stromal keratitis in the rabbit eye model. Invest Ophthalmol Vis Sci 44:2529–2534CrossRefPubMedGoogle Scholar
  3. Benzie IFF, Strain JJ (1996) The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Anal Biochem 239:70–76CrossRefPubMedGoogle Scholar
  4. Breitbart M, Rohwer F (2005) Here a virus, there a virus, everywhere the same virus. Trends Microbiol 13:278–274CrossRefPubMedGoogle Scholar
  5. Cahard D, McGuigan C, Balzarini J (2004) Aryloxy phosphoramidate triesters as pro-tides. Mini Rev Med Chem 4:371–381CrossRefPubMedGoogle Scholar
  6. Chadra Sekhar K, Thaslim Basha SK, Bhuvaneswar C, Bhaskar BV, Rajendra W, Naga Raju C, Ghosh SK (2015) Didanosine phosphoramidates: synthesis, docking to viral NA, antibacterial and antiviral activity. Med Chem Res 24:209–219CrossRefGoogle Scholar
  7. Chillemi R, Russo D, Sciuto S (1998) Chemoenzymatic synthesis of lysophos-phatidylnucleosides. J Org Chem 63:3224–3229CrossRefGoogle Scholar
  8. Chu CK, Baker DC (1993) Nucleosides and nucleotides as antitumor and antiviral agents. Plenum Press, New York, NYCrossRefGoogle Scholar
  9. Congiatu C, McGuigan C, Jiang WG, Davies G, Mason MD (2005) Naphthyl phosphoramidate derivatives of bvdu as potential anticancer agents: design, synthesis and biological evaluation. Nucleos Nucleot Nucl 24:485–489CrossRefGoogle Scholar
  10. Czegledi A, Ujvari D, Somogyi E, Wehmann E, Werner O, Lomniczi B (2006) Third genome size category of avian paramyxovirus serotype 1 (Newcastle disease virus) and evolutionary implications. Virus Res 120:36–48CrossRefPubMedGoogle Scholar
  11. Dastmalchi S, Hamzeh-Mivehroud M, Ghafourian T, Hamzeiy H (2008) Molecular modeling of histamine H3 receptor and QSAR studies on arylbenzofuran derived H3 antagonists. J Mol Graph Model 26:834–844CrossRefPubMedGoogle Scholar
  12. Davies RJ, Pierce AC, Forster C, Grey R, Xu J, Arnost M, Choquette D, Galullo V, Tian SK, Henkel G, Chen G, Heidary DK, Ma J, Stuver-Moody C, Namchuk M (2011) Design, synthesis, and evaluation of a novel dual FMS-like tyrosine kinase 3/stem cell factor receptor (FLT3/c-KIT) inhibitor for the treatment of acute myelogenous leukemia. J Med Chem 54:7184–7192CrossRefPubMedGoogle Scholar
  13. De Clercq E (1990) Recent advances in the search for selective antiviral agents. Adv Drug Res 17:1–59Google Scholar
  14. Dortmans CFM, Koch G, Peter RJM, Peeters BPH (2011) Virulence of Newcastle disease virus: what is known so far. Vet Res 42:122–133CrossRefPubMedPubMedCentralGoogle Scholar
  15. Dinesh S, Shikha G, Bhavana G, Nidhi S, Dileep S (2012) Biological activities of purine analogues: a review. J Pharm Sci Innov 2:29–34Google Scholar
  16. Easterbrook P, Wood MJ (1994) Successors to acyclovir. J Antimicrob Chemother 34:307–311CrossRefPubMedGoogle Scholar
  17. Fiddian AP (1996) Antiviral drugs in development for herpes zoster. Scand J Infect Dis Suppl 100:51–54PubMedGoogle Scholar
  18. Gao H, Mitra A (2001) Regioselective synthesis of acyclovir and its various prodrugs. Synth Commun 31:1399–1419CrossRefGoogle Scholar
  19. Goslinski T, Golankiewicz B, De Clercq E, Balzarini J (2002) Synthesis and biological activity of strongly fluorescent tricyclic analogues of acyclovir and ganciclovir. J Med Chem 45:5052–5057CrossRefPubMedGoogle Scholar
  20. Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JKSR (1982) Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem 126:131–138CrossRefPubMedGoogle Scholar
  21. Gubareva LV (2004) Molecular mechanisms of influenza virus resistance to neuraminidase inhibitors. Virus Res 103:199–203CrossRefPubMedGoogle Scholar
  22. Harshalata D, Dhongade HJ, Kavita C (2015) Pharmacological potentials of pyrimidine derivative: a review. Asian J Pharm Clin Res 8:171–177Google Scholar
  23. Herdewijn PAMM (1992) Novel nucleoside strategies for anti-HIV and anti-HSV therapy. Antivir Res 19:1–14CrossRefPubMedGoogle Scholar
  24. Karpenko IL, Jasko MV, Andronova VL, Kukhanova AVIMK, Galegov GA, Skoblov YS (2003) Synthesis and antiherpetic activity of acyclovir phosphonates. Nucleos Nucleot Nucl 22:319–328CrossRefGoogle Scholar
  25. Kim DK, Lee N, Im GJ, Kim HT, Kim KH (1998) Synthesis and evaluation of 2-amino-6-fluoro-9-(2-hydroxyethoxymethyl)purine esters as potential prodrugs of acyclovir. Bioorg Med Chem 6:2525–2530CrossRefPubMedGoogle Scholar
  26. Kumar P, Khanna M, Srivastava V, Tyagi YK, Raj HG, Ravi K (2005) Effect of quercetin supplementation on lung antioxidants after experimental influenza virus infection. Exp Lung Res 31:449–459CrossRefPubMedGoogle Scholar
  27. Lamb RA (1993) Paramyxovirus fusion: a hypothesis for changes. Virology 197:1–11CrossRefPubMedGoogle Scholar
  28. Laskowski RA (2001) PDBsum: summaries and analyses of PDB structures. Nucleic Acids Res 29:221–222CrossRefPubMedPubMedCentralGoogle Scholar
  29. Marcocci L, Maguire JJ, Droy-Lefaix MT, Packer L (1994) The nitric oxide-scavenging properties of ginkgo biloba extract EGB 761. Biochem Biophys Res Commun 201:748–755CrossRefPubMedGoogle Scholar
  30. Mayo MA (2002) A summary of taxonomic changes recently approved by ICTV. Arch Virol 147:1655–1663CrossRefPubMedGoogle Scholar
  31. McGuigan C, Cahard D, Sheeka HM, De Clercq E, Balzarini J (1996) Synthesis and biological activity of aromatic amino acid phosphoramidates of 5-fluoro-2′-deoxyuridine and 1-β-arabinofurano- sylcytosine: evidence of phosphoramidase activity. J Med Chem 39:1748–1753CrossRefPubMedGoogle Scholar
  32. McGuigan C, Harris SA, Daluge SM, Gud mundsson KS, McLean EW, Burnette TC, Marr H, Hazen R, Condreay LD, Johnson L, De Clercq E, Balzarini J (2005) Application of phosphoramidate pronucleotide technology to abacavir leads to a significant enhancement of antiviral potency. J Med Chem 48:3504–3515CrossRefPubMedGoogle Scholar
  33. Ostrowski T, Golankiewicz B, De Clercq E, Balzarini J (2005) Fluorosubstitution and 7-alkylation as prospective modifications of biologically active 6-aryl derivatives of tricyclic acyclovir and ganciclovir analogues. Bioorg Med Chem 13:2089–2096CrossRefPubMedGoogle Scholar
  34. Ostrowski T, Golankiewicz B, De Clercq E, Andrei G, Snoeck R (2009) Synthesis and anti-VZV activity of 6-heteroaryl derivatives of tricyclic acyclovir and 9-{[cis-1′,2′-bis(hydroxymethyl)cycloprop-1′-yl]methyl}guanine analogues. Eur J Med Chem 44:3313–3317CrossRefPubMedGoogle Scholar
  35. Perrone P, Luoni GM, Kelleher MR, Daverio F, Angell A, Mulready S, Congiatu C, Rajyaguru S, Martin JA, Le Pogam S, Najera I, Klumpp K, Smith DB, McGuigan C (2007) Application of the phosphoramidate protide approach to 4′-azidouridine confers sub-micromolar potency versus hepatitis c virus on an inactive nucleoside. J Med Chem 50:1840–1849CrossRefPubMedGoogle Scholar
  36. Rajbhandari M, Wegner U, Julich M, Schopke T, Mentel R (2001) Screening of nepalese medicinal plants for antiviral activity. J Ethnopharm 74:251–255CrossRefGoogle Scholar
  37. Rao AJ, Rao VK, Rao PV, Raju CN, Kumar GS (2010) Synthesis and bioactivity of phosphorylated derivatives of stavudine. Eur J Chem 1:297–301CrossRefGoogle Scholar
  38. Rao VK, Reddy SS, Babu KR, Kumar KH, Kumar GS, Raju CN (2011) Synthesis and cytotoxicity evaluation of phosphorylated derivatives of ribavirin. J Korean Chem Soc 55:952–959CrossRefGoogle Scholar
  39. Robins RK (1984) The potential of nucleotide analogs as inhibitors of retroviruses and tumors. Pharm Res 1:11–18CrossRefPubMedGoogle Scholar
  40. Santos CR, Capela R, Pereira CSGP, Valente E, Gouveia L, Pannecouque C, De Clercq E, Moreira R, Gomes P (2009) Structure–activity relationships for dipeptide prodrugs of acyclovir: implications for prodrug design. Eur J Med Chem 44:2339–2346CrossRefPubMedGoogle Scholar
  41. Schaeffer HJ, Beauchamp L, De Miranda P, Elion GB, Bauer DJ, Collins P (1978) 9-(2-Hydroxyethoxymethyl)guanine activity against viruses of the herpes group. Nature 272:583–585CrossRefPubMedGoogle Scholar
  42. Sekhar KC, Rao DS, Mouli KC, Vijaya T, Raju CN (2014) Phosphorylated ganciclovir derivatives: design, synthesis and in vitro and in vivo immunomodulatory activity. Med Chem Res 23:2242–2251CrossRefGoogle Scholar
  43. Sinko PJ, Balimane PV (1998) Carrier-mediated intestinal absorption of valacyclovir, the l-valyl ester prodrug of acyclovir. 1. Interactions with peptides, organic anions and organic cations in rats. Biopharm Drug Dispos 19:209–217CrossRefPubMedGoogle Scholar
  44. Sippl W (2002) Development of biologically active compounds by combining 3D QSAR and structure-based design methods. J Comput Aided Mol Des 16:825–830CrossRefPubMedGoogle Scholar
  45. Stephen KT, David B, Wendy S (2002) Valacyclovir for herpus simplex virus infection: long-term safety and sustained efficacy after 20 years’ experience with acyclovir. J Infect Dis Suppl 186:S40–S46CrossRefGoogle Scholar
  46. Suresh KA, Subbaiah KCV, Lavanya R, Chandrasekhar K, Naga Raju C, Suresh Kumar M, Rajendra W, Lokanatha V (2016a) Design, synthesis, and biological evaluation of novel phosphorylated abacavir derivatives as antiviral agents against Newcastle disease virus infection in chicken. Appl Biochem Biotechnol. doi: 10.1007/s12010-016-2104-x
  47. Suresh KA, Subbaiah KCV, Thaslim Basha SK, Naga Raju C, Suresh Kumar M, Rajendra W, Lokanatha V (2016b) Synthesis and antiviral activity of novel phosphorylated derivatives of didanosine against Newcastle disease virus in chicken. Arch Pharm Chem Life Sci 349:1–14CrossRefGoogle Scholar
  48. Su-Ting H, Yong-Zhong D, Hong Y, Xing-Guo Z, Jing M, Fu-De C, Fu-Qiang H (2011) Synthesis and anti-hepatitis B virus activity of acyclovir conjugated stearic acid-g-chitosan oligosaccharide micelle. Carbohydr Polym 83:1715–1722CrossRefGoogle Scholar
  49. Wutzler P, Thust R (2001) Genetic risks of antiviral nucleoside analogues-a survey. Antiviral Res 49:55–74CrossRefPubMedGoogle Scholar
  50. Yang C, Gao H, Mitra AK (2001) Chemical stability, enzymatic hydrolysis, and nasal uptake of amino acid ester prodrugs of acyclovir. J Pharm Sci 90:617–624CrossRefPubMedGoogle Scholar
  51. Yen GC, Chen HY (1995) Antioxidant activity of various tea extracts in relation to their antimut agenicity. J Agric Food Chem 43:27–32CrossRefGoogle Scholar
  52. Young M, Alders R, Grimes S, Spradbrow P, Dias P, Silva A, Lobo Q (2002) Controlling Newcastle disease in village chickens: a laboratory manual ACIAR monograph, no. 87, p 142Google Scholar
  53. Zakirova NF, Shipitsynl AV, Jasko MV, Kochetkov SN (2011) Phosphoramidate derivatives of acyclovir, inhibitors of herpes virus replication. Russ J Bioorg Chem 37:578–585CrossRefGoogle Scholar
  54. Zakirova NF, Shipitsyn AV, Jasko MV, Prokofjeva MM, Andronova VL, Galegov GA, Prassolov VS, Kochetkov SN (2012) Phosphoramidate derivatives of acyclovir: synthesis and antiviral activity in HIV-1 and HSV-1 models in vitro. Bioorg Med Chem 20:5802–5809CrossRefPubMedGoogle Scholar
  55. Zemlicka J (2002) Lipophilic phosphoramidates as antiviral pronucleotides. Biochim Biophys Acta Mol Basis Dis 1587:276–286CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Subba Rao Devineni
    • 1
  • Madhava Golla
    • 1
  • Thaslim Basha Shaik
    • 1
  • Janardhan Avilala
    • 2
  • Madhu Sudhana Saddala
    • 3
  • Narasimha Golla
    • 2
  • Naga Raju Chamarthi
    • 1
    Email author
  1. 1.Department of ChemistrySri Venkateswara UniversityTirupatiIndia
  2. 2.Department of VirologySri Venkateswara UniversityTirupatiIndia
  3. 3.Department of BioinformaticsSri Venkateswara UniversityTirupatiIndia

Personalised recommendations