Journal of Chemical Biology

, Volume 9, Issue 1, pp 31–40 | Cite as

Synthesis, antibacterial studies, and molecular modeling studies of 3,4-dihydropyrimidinone compounds

  • Vanitha Ramachandran
  • Karthiga Arumugasamy
  • Sanjeev Kumar Singh
  • Naushad Edayadulla
  • Penugonda Ramesh
  • Sathish-Kumar Kamaraj
Original Article


The syntheses of dihydropyrimidinones (DHPMs) using solvent-free grindstone chemistry method. All the synthesized compounds exhibited significant activity against pathogenic bacteria. The current effort has been developed to obtain new DHPM derivatives that focus on the bacterial ribosomal A site RNA as a drug target. Molecular docking simulation analysis was applied to confirm the target specificity of DHPMs. The crystal structure of bacterial 16S rRNA and human 40S rRNA was taken as receptors for docking. Finally, the docking score, binding site interaction analysis revealed that DHPMs exhibit more specificity towards 16S rRNA than known antibiotic amikacin. Accordingly, targeting the bacterial ribosomal A site RNA with potential drug leads promises to overcome the bacterial drug resistance. Even though, anti-neoplastic activities of DHPMs were also predicted through prediction of activity spectra for substances (PASS) tool. Further, the results establish that the DHPMs can serve as perfect leads against bacterial drug resistance.


Grindstone chemistry Ribosomal RNA Bioactivity Molecular modeling 



The author SKS thank the Department of Science and Technology (DST) for Fast Track grant (SR/FT/CS-66/2010) and the Department of Biotechnology (DBT), New Delhi, BT/502/NE/TBP/ 2013. One of the authors, SKK, thanks the Conacyt and SEP of Mexican Govt.

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

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ESM 1 (DOCX 13 kb)
12154_2015_142_MOESM2_ESM.docx (13 kb)
ESM 2 (DOCX 12 kb)
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ESM 3 (DOCX 15 kb)


  1. 1.
    Bachi BB (2002) Resistance mechanisms of Gram-positive bacteria. Int J Med Microbiol 292:27–35CrossRefGoogle Scholar
  2. 2.
    Zhou J, Wang G, Zhang L, Ye X (2007) Modifications of aminoglycoside antibiotics targeting RNA. Med Res Rev 27:279–316CrossRefGoogle Scholar
  3. 3.
    Li Y, Shen J, Sun X, Li W, Liu G, Tang Y (2010) Accuracy assessment of protein-based docking programs against RNA targets. J Chem Inf Model 50:1134–1146CrossRefGoogle Scholar
  4. 4.
    Philips A, Milanowska K, Lach G, Bujnicki JM (2013) LigandRNA: computational predictor of RNA-ligand interactions. RNA 19:1605–1616CrossRefGoogle Scholar
  5. 5.
    Ma C, Baker NA, Joseph S, McCammon JA (2002) Binding of aminoglycoside antibiotics to the small ribosomal subunit: a continuum electrostatics investigation. J Am ChemSoc 124:1438–1442CrossRefGoogle Scholar
  6. 6.
    Fullea S, Gohlke H (2009) Molecular recognition of RNA: challenges for modelling interactions and plasticity. J Mol Recognit. doi: 10.1002/jmr.1000 Google Scholar
  7. 7.
    Brands M, Endermann R, Gahlmann R, Kruger J, Raddatz S (2003) Dihydropyrimidinones—a new class of anti-staphylococcal antibiotics. Bioorg Med Chem Lett 13:241–245CrossRefGoogle Scholar
  8. 8.
    Kappe CO (1993) 100 years of the biginelli dihydropyrimidine synthesis. Tetrahedron 49(32):6937–6963CrossRefGoogle Scholar
  9. 9.
    Kappe C, Kumar OD, Varma RS (1999) Microwave-assisted high-speed parallel synthesis of 4-aryl-3,4-dihydropyrimidin-2(1H)-ones using a solventless Biginelli condensation protocol. Synthesis 10:1799–803CrossRefGoogle Scholar
  10. 10.
    Stefani HA, Gatti PM (2000) 3,4-Dihydropyrimidin-2(1H)-ones: fast synthesis under microwave irradiation in solvent free conditions. Synth Commun 30:2165–2173CrossRefGoogle Scholar
  11. 11.
    Kappe CO (2000) Recent advances in the Biginelli dihydropyrimidine synthesis. New tricks from an old dog. Acc Chem Res 33(12):879–888CrossRefGoogle Scholar
  12. 12.
    De SK, Gibbs RA (2005) Ruthenium (III) chloride-catalyzed one-pot synthesis of 3,4-dihydro­pyrimidin-2-(1H)-ones under solvent-free conditions. Synthesis 11:1748–50CrossRefGoogle Scholar
  13. 13.
    Kappe CO, Stadler A (2004) The Biginelli dihydropyrimidine synthesis. Org React 63(1):1–116Google Scholar
  14. 14.
    Jayakumar S, Shabeer TK (2011) Multicomponent Biginelli synthesis of 3,4-dihydropyrimidin-2(1H)-ones by grindstone technique and evaluation of their biological properties. J Chem Pharm Res 3(6):1089–1096Google Scholar
  15. 15.
    Deshmukh MB, Prashant AV, Jadhav SD, Mali AR, Jagtap SS, Deshmukh SA (2007) An efficient simple one pot synthesis of dihydropyrimidine-2 (1H) ones using phosphorus pentoxide. Indian J Chem 46B(1545):48Google Scholar
  16. 16.
    LigPrep, version 2.6. (2012) Schrödinger, LLC, New York, NYGoogle Scholar
  17. 17.
    Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W (2013) Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des 27:221–234CrossRefGoogle Scholar
  18. 18.
    Friensner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, RepaskyMp KEH, Shelley M, Perry JK, Shaw DE, Francis P, Shenkin PS (2004) Glide: a new approach for rapid accurate docking and scoring method and assessment of docking accuracy. J Med Chem 47:1739–1749CrossRefGoogle Scholar
  19. 19.
    Vijayalakshmi P, Selvaraj C, Singh SK, Nisha J, Saipriya K, Daisy P (2012) Exploration of the binding of DNA binding ligands to Staphylococcal DNA through QM/MM docking and molecular dynamics simulation. J Biomol Struct Dyn 1–11Google Scholar
  20. 20.
    Glide, version 5.8. 2012 Schrödinger, LLC, New York, NYGoogle Scholar
  21. 21.
    QikProp, version 3.5. 2012 Schrödinger, LLC, New York, NYGoogle Scholar
  22. 22.
    Tripathi SK, Selvaraj C, Singh SK, Reddy KK (2012) Molecular docking, QPLD, and ADME prediction studies on HIV-1 integrase leads. Med Chem Res. doi: 10.1007/s00044-011-9940-6 Google Scholar
  23. 23.
    Lagunin A, Stepanchikova A, Filimonov D, Poroikov V (2000) PASS: prediction of activity spectra for biologically active substances. Bioinformatics 16:747–748CrossRefGoogle Scholar
  24. 24.
    Poroikov VV, Filimonov DA, Ihlenfeldt WD, Gloriozova TA, Lagunin AA, Borodina YV, Stepanchikova AV, Nicklaus MC (2002) PASS biological activity spectrum predictions in the enhanced open NCI database browser. J Chem Inf Comput Sci 43:228–236CrossRefGoogle Scholar
  25. 25.
    Sadym A, Lagunin A, Filimonov D, Poroikov V (2003) Prediction of biological activity spectra via the internet. SAR QSAR Environ Res 14:339–347CrossRefGoogle Scholar
  26. 26.
    Mayer TU, Kapoor TM, Haggarty SJ, King RW, Schreiber SL, Mitchison TJ (1999) Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 286(5441):971–974CrossRefGoogle Scholar
  27. 27.
    Garcia-Saez I, DeBonis S, Lopez R, Trucco F, Rousseau B, Thuéry P, Kozielski F (2007) Structure of human Eg5 in complex with a new monastrol-based inhibitor bound in the R configuration. J Biol Chem 282(13):9740–9747CrossRefGoogle Scholar
  28. 28.
    Dhumaskar KL, Meena SN, Ghadi SC, Tilve SG (2014) Graphite catalyzed solvent free synthesis of dihydropyrimidin-2(1H)-ones/thiones and their antidiabetic activity. Bioorg Med Chem Lett 24:2897–2899CrossRefGoogle Scholar
  29. 29.
    McCgaughey GB, Gagne M, Rappe AK (1998) π-Stacking interactions. Alive and well in proteins. J BiolChem 273:15458–15463Google Scholar
  30. 30.
    Dougherty DA (2007) Cation-π interactions involving aromatic amino acids. J Nutr 137:1504S–1508SGoogle Scholar
  31. 31.
    Daldrop P, Reyes FE, Robinson DA, Hammond CM, Lilley DM, Batey RT, Brenk R (2011) Novel ligands for a purine riboswitch discovered by RNA-ligand docking. Chem Biol 18:324–335CrossRefGoogle Scholar
  32. 32.
    Kadir FA, Kassim NM, Abdulla MA, Yehye WA (2013) PASS-predicted Vitex negundo activity: antioxidant and antiproliferative properties on human hepatoma cells-an in vitro study. BMC Complement Alternat Med 13:343CrossRefGoogle Scholar
  33. 33.
    Kim J, Park C, Ok T, So W, Jo M, Seo M, Kim Y, Sohn JH, Park Y, Ju MK, Kim J, Han SJ, Kim TH, Cechetto J, Nam J, Sommer P, No Z (2012) Discovery of 3,4-dihydropyrimidin-2(1H)-ones with inhibitory activity against HIV-1 replication. Bioorg Med Chem Lett 22(5):2119–2124CrossRefGoogle Scholar
  34. 34.
    Jalali M, Mahdavi M, Memarian HR, Ranjbar M, Soleymani M, Fassihi A, Abedi D (2012) Antimicrobial evaluation of some novel derivatives of 3,4-dihydropyrimidine-2(1H)-one. Res Pharm Sci 7(4):243–247Google Scholar
  35. 35.
    Törün T, Güngör G, Özmen I, Bölükba Y, Maden E, Bıçakçı B, Ataç G, Sevim T, Tahaoglu K (2005) Side effects associated with the treatment of multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 9(12):1373–1377Google Scholar
  36. 36.
    Pickering LK, Gearhart P (1979) Effect of time and concentration upon interaction between gentamicin, tobramycin, netilmicin, or amikacin and carbenicillin or ticarcillin. Antimicrob Agents Chemother 15(4):592–596CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Vanitha Ramachandran
    • 1
  • Karthiga Arumugasamy
    • 2
  • Sanjeev Kumar Singh
    • 3
  • Naushad Edayadulla
    • 4
  • Penugonda Ramesh
    • 1
  • Sathish-Kumar Kamaraj
    • 5
  1. 1.Department of Natural Products Chemistry, School of ChemistryMadurai Kamaraj UniversityMaduraiIndia
  2. 2.Department of ZoologyThiagarajar CollegeMaduraiIndia
  3. 3.Computer Aided Drug Designing and Molecular Modeling Laboratory, Department of BioinformaticsAlagappa UniversityKaraikudiIndia
  4. 4.School of Chemical EngineeringYeungnam UniversityGyeongsanRepublic of Korea
  5. 5.Ingeniería en Energía, Universidad Politécnica de AguascalientesAguascalientesMexico

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