Medicinal Chemistry Research

, Volume 23, Issue 5, pp 2554–2563 | Cite as

Descriptors requirement for QSAR analysis of pyrazolo-triazolo-pyrimidine derivative as human A3 receptor antagonists: design of novel furan derivatives and validation by docking

  • Laxman M. PrajapatiEmail author
  • Jimish R. Patel
  • Vijay K. Parmar
Original Research


A quantitative structure activity relationship study was carried out on pyrazolo-triazolo-pyrimidines derivatives to establish the descriptor requirement for the A3 receptor antagonistic activity. In total, seven models with high predictive power were developed using sequential multiple linear regression. The best model was selected having excellent predictivity with \(R_{\text{pred}}^{{^{ 2} }}\) and \(r_{\text{m}}^{2}\) (overall) of 0.903 and 0.854, respectively. The geometrical descriptors like WHIM and 2D-autocorrelation have a positive effect on the potency of the compound. The Sanderson electronegativity has a major effect on the binding of this series with the human A3 receptors. The QSAR study was found to be consistent with the docking study.


A3 receptor Pyrazolo-triazolo-pyrimidines 2D-autocorrelation WHIM Sanderson electronegativity Docking 


  1. Baraldi PG, Cacciari B, Spalluto G, Bergonzoni M, Dionisotti S (1998) Design, synthesis, and biological evaluation of a second generation of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as potent and selective A2A adenosine receptor antagonists. J Med Chem 41:2126–2133CrossRefPubMedGoogle Scholar
  2. Baraldi PG, Cacciari B, Romagnoli R, Spalluto G, Klotz KN (1999) Pyrazolo[4,3-e] 1,2,4-triazolo[1,5-c]pyrimidine derivatives as highly potent and selective human A3 adenosinereceptor antagonists. J Med Chem 42:4473–4478CrossRefPubMedGoogle Scholar
  3. Baraldi PG, Cacciari B, Romagnoli R, Merighi S, Varani K (2000a) A3 adenosine receptor ligands: history and perspectives. Med Res Rev 20:103–128CrossRefPubMedGoogle Scholar
  4. Baraldi PG, Cacciari B, Romagnoli R, Spalluto G, Moro S (2000b) Pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives as highly potent and selective human A3 adenosine receptor antagonists: influence of the chain at the N8 pyrazolo nitrogen. J Med Chem 43:4768–4780CrossRefPubMedGoogle Scholar
  5. Baraldi PG, Cacciari B, Borean PA, Varanin K, Pastorin G (2002a) Pyrazolo-triazolo-pyrimidinederivatives as adenosine receptor antagonists: a possible template for adenosine receptor subtypes? Curr Pharm Des 8:2299–2332CrossRefPubMedGoogle Scholar
  6. Baraldi PG, Cacciari B, Moro S, Spalluto G, Pastorin G (2002b) Synthesis, biological activity, and molecular modeling investigation of new pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives as human A3 adenosine receptor antagonists. J Med Chem 45:770–780CrossRefPubMedGoogle Scholar
  7. Broto P, Moreau G, Vandycke C (1984) Molecular structures: perception, autocorrelation descriptor and SAR studies. Eur J Med Chem 19:71–78Google Scholar
  8. CS Chem Office (2004) Version 8.0, Cambridge Soft Corporation, Software Publishers Association, Washington, DCGoogle Scholar
  9. Fredholm BB, Abbracchio MP, Burnstock G, Dubyak GR, Harden TK, Jacobson KA, Schwabe U, Williams M (1997) Towards a revised nomenclature for P1 and P2 receptors. Trends Pharmacol Sci 18:79–82PubMedCentralCrossRefPubMedGoogle Scholar
  10. Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J (2001) International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53:527–552PubMedGoogle Scholar
  11. Gao ZG et al (2002a) Identification by site-directed mutagenesis of residues involved in ligand recognition and activation of the human A3 adenosine receptor. J Biol Chem 277:19056–19063CrossRefPubMedGoogle Scholar
  12. Gao ZG, Kim SK et al (2002b) Structural determinants of A3 adenosine receptor activation—nucleoside ligands at the agonist/antagonist boundary. J Med Chem 45:4471–4484CrossRefPubMedGoogle Scholar
  13. Gupta AK, Arockia BM, Kaskhedikar SG (2004) VALSTAT: Validation Program for Quantitative Structure Activity Relationship Studies. Ind J Pharm Sci 66:396–402Google Scholar
  14. Haas HL, Selbach O (2000) Functions of neuronal adenosine receptors. Naunyn-Schmiedeberg’s Arch Pharmacol 362:375–381CrossRefGoogle Scholar
  15. Jacobson KA (1998) Adenosine A3 receptors: novel ligands and paradoxical effects. Trends Pharmacol Sci 19:184–191PubMedCentralCrossRefPubMedGoogle Scholar
  16. Jiang Q, Van Rhee AM, Kim J, Yehle S, Wess J (1996) Neoceptor concept based on molecular complementarity in GPCRs: a mutant adenosine A3 receptor with selectively enhanced affinity for amine-modified nucleosides. Mol Pharmacol 50:512–521PubMedCentralPubMedGoogle Scholar
  17. Jiang Q, Lee BX, Glashofer M, van Rhee AM, Jacobson KA (1997) Mutagenesis reveals structure–function parallels between human A-adenosine receptors and the biogenic amine family. J Med Chem 40:2588–2595PubMedCentralCrossRefPubMedGoogle Scholar
  18. Kishore PD, Balakumar C, Rao AR, Roy PP, Roy K (2011) QSAR of adenosine receptor antagonists: exploring physicochemical requirements for binding of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives with human adenosine A3 receptor subtype. Bioorg Med Chem Lett 21:818–823CrossRefGoogle Scholar
  19. Moreau G, Broto P (1980) The autocorrelation of atopological structure: a new molecular descriptor. Nouveau Journal de Chimie 4:359–360Google Scholar
  20. Moro S, Paolo B, Francesca D, Cristina F, Pastorin G, Cacciari B, Baraldi PG, Varani K, Borea PA, Spalluto GJ (2005) Combined target-based and ligand-based drug design approach as a tool to define a novel 3D-pharmacophore model of human A3 adenosine receptor antagonists: pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives as a key study. J Med Chem 48:152–162CrossRefPubMedGoogle Scholar
  21. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) Auto Dock4 and AutoDock Tools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791PubMedCentralCrossRefPubMedGoogle Scholar
  22. Ojha PK, Mitra I, Das RN, Roy K (2011) Further exploring r m2 metrics for validation of QSPR models. Chemom Intell Lab Syst 107:194–205CrossRefGoogle Scholar
  23. Pastorin G, Da Ros T, Spalluto G, Deflorian F, Moro S (2003) Pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidinederivatives as adenosine receptor antagonists: influence of the N5 substituent on the affinity at the human A3 and A2B adenosine receptor subtypes. J Med Chem 46:4287–4296CrossRefPubMedGoogle Scholar
  24. Prajapati LM, Patel MJ, Parmar VK, Patel JR (2012) Development of QSAR model for prediction of fold selectivity of phenyl benzoxazole as estrogen receptor inhibitors. Med Chem Res 21:3681–3686CrossRefGoogle Scholar
  25. Shryock JC, Belardinelli L (1997) Adenosine and adenosine receptors in the cardiovascular system: biochemistry physiology and pharmacology. Am J Cardiol 79:2–10CrossRefPubMedGoogle Scholar
  26. Stephen C, Peterangel O, Paul G, Seybol D (2004) Synergistic interactions among QSAR descriptors Int. J Quantum Chem 96:1–9CrossRefGoogle Scholar
  27. Todeschini R, Consonni V (2001) Dragon software (version 1.11). Milano Chemometrics and QSAR Group, MilanoGoogle Scholar
  28. Todeschini R, Gramatica P (1998) 3D QSAR in drug design. In: Kubinyi H, Folkers G, Martin YC (eds), Kluwer/ESCOM, Dordrecht, 2: 355–360Google Scholar
  29. Todeschini R, Lasagni M, Marengo E (1994) New molecular descriptors for 2D- and 3D-structures. Theory J Chemom 8:263–273CrossRefGoogle Scholar
  30. Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J Comput Chem 31:455–461PubMedCentralPubMedGoogle Scholar
  31. von Lubitz DK, Ye W, McClellan J, Lin RC, Ann NY (1999) Stimulation of adenosine A3 receptors in cerebral ischemia. Neuronal death, recovery, or both? Acad. Sci. 890:93–106CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Laxman M. Prajapati
    • 1
    Email author
  • Jimish R. Patel
    • 1
  • Vijay K. Parmar
    • 2
  1. 1.Department of Pharmaceutical ChemistryShri B M Shah College of Pharmaceutical Education and ResearchModasaIndia
  2. 2.Ramanbhai Patel College of PharmacyCharotar University of Science and TechnologyChangaIndia

Personalised recommendations