• BABASAHEB D SONAWANE Department of Chemistry, Karmaveer Bhaurao Patil Mahavidyalaya, Pandharpur, Maharashtra, India.
  • VIKAS D D SONAWANE Department of Chemistry, Smt. Kusumtai Rajarambapu Patil Kanya Mahavidyalaya, Islampur, Maharashtra, India.
  • KAILAS D SONAWANE Department of Microbiology Shivaji University, Kolhapur, Maharashtra, India.
  • MARUTI D J DHANAVADE Department of Microbiology Shivaji University, Kolhapur, Maharashtra, India.
  • CHETAN B AWARE Department of Biotechnology, Shivaji University, Kolhapur, Maharashtra, India.
  • SHARAD K AWATE Department of Chemistry, Karmaveer Bhaurao Patil Mahavidyalaya, Pandharpur, Maharashtra, India.
  • SURESH V PATIL Department of Chemistry, Karmaveer Bhaurao Patil Mahavidyalaya, Pandharpur, Maharashtra, India.


Objectives: The present protocol deals with zirconocene dichloride (Cp2ZrCl2) catalyzed synthesis of pyrano[2,3-d]pyrimidinediones through one-pot multicomponent reactions of aromatic aldehydes with malononitrile and barbituric acid at ambient temperature. All the synthesized compounds were characterized and evaluated for antibacterial, antifungal, and antioxidant activities. Furthermore, a molecular docking was carried out to reveal the atomic insights between synthesized compounds and carotenoid dehydrosqualene synthase (PDB ID: 3ACX).

Methods: All the synthesized compounds were evaluated for their in vitro antimicrobial activity by diffusion method. Antioxidant activities such as 1,1-diphenyl-2-picrylhydrazyl and radical scavenging activity. A mixture of barbituric acid 1 (1 mmol), malononitrile 2 (1 mmol), benzaldehyde 3a (1 mmol), ethanol (5 mL), and Cp2ZrCl2 (5 mol %) was stirred at ambient temperature for specified time. After completion of reaction as indicated by thin-layer chromatography, the obtained crude product was filtered and purified by column chromatography on silica gel (Merck, 60–120 mesh) using ethyl acetate:pet. ether to afford pure product which was then characterized by spectroscopic methods such by FTIR, nuclear magnetic resonance (1H NMR), 13C NMR, and mass spectroscopy.

Results: All the synthesized pyrano[2,3-d]pyrimidinediones were characterized by spectroscopic analysis. The results revealed that pyrano[2,3-d] pyrimidinediones (4 a-k) displayed the zone of inhibition in the range of 3–13 mm. The most active compound 4b displayed largest zone of inhibition of 13 mm for Escherichia coli (NCIM-2832) and 9 mm for Bacillus subtilis (NCIM-2635). The antifungal and antioxidant activity of all synthesized pyrano[2,3-d]pyrimidinediones (4a-k) showed moderate to good activity. Molecular docking studies suggest that pyrano[2,3-d]pyrimidinediones might inhibit the carotenoid dehydrosqualene synthase activity.

Conclusion: All the synthesized pyrano[2,3-d]pyrimidinediones display moderate to good antibacterial, antifungal, and antioxidant activity. This molecular docking studies supported that pyrano[2,3-d]pyrimidinediones might inhibit the carotenoid dehydrosqualene synthase (PDB ID: 3ACX).

Keywords: Zirconocene dichloride, Pyrano[2,3-d]pyrimidinediones, Antimicrobial, Antioxidant, Carotenoid dehydrosqualene synthase, Molecular docking.

Author Biography

BABASAHEB D SONAWANE, Department of Chemistry, Karmaveer Bhaurao Patil Mahavidyalaya, Pandharpur, Maharashtra, India.

Associate Professor


1. a) Schwartz J, Labinger JA. Hydrozirconation: A new transition metal reagent for organic synthesis. Angew Chem 1976;88:402 9. b) Hart DW, Blackburn TF, Schwartz J. Hydrozirconation. III stereospecific and regioselective functionalization of alky lacetylenes via vinyl zirconium(IV) intermediates. J Am Chem Soc 1975;97:679-80. c) Hart DW, Schwartz J. Hydrozirconation. Organic synthesis via organozirconium intermediates. Synthesis and rearrangement of alkyl zirconium (IV) complexes and their reaction with electrophiles. J Am Chem Soc 1974;96:8115-16.
2. a) Milani MA, DeSouza MO, Dsouza RF. NiP^O and [Cp2ZrCl2/MAO] as a versatile dual-function catalyst system for in situ polymerization of ethylene to linear low-density polyethylene (LLDPE). Catal Commun 2010;11:1094-7. b) Li KT, Dai CL, Li CY. Synthesis of linear low density polyethylene with a nano-sized silica +supported Cp2ZrCl2/MAO catalyst. Polym Bull 2010;64:749-59. c) Li KT, Dai CL, Kuo CW. Ethylene polymerization over a nano-sized silica supported Cp2ZrCl2/MAO catalyst. Catal Commun 2007;8:1209-13.
3. a) Takahashi T, Kondakov DY, Suzuki N. Novel type of zirconium-catalyzed or -promoted cyclization reaction. Organometallics 1994;13:3411-2. b) Negishi EI, Takahashi T.Patterns of stoichiometric and catalytic reactions of organozirconium and related complexes of synthetic interest. Acc Chem Res 1994;27:124-30.
4. a) Li CJ. Organic reactions in aqueous media with a focus on carbon carbon bond formations: A decade update. Chem Rev 2005;105:3095-66. b) Corma A, Garcia H. Lewis acids: From conventional homogeneous to green homogeneous and heterogeneous catalysis. Chem Rev Am Chem Soc 2003;103:4307-66. c) Okuhara T. Water-tolerant solid acid catalysts. Am Chem Soc Chem Rev 2002;102:3641-66. d) Kobayashi S, Sugiura M, Kitagawa H, William WL. Lam rare-earth metal triflates in organic synthesis. Am Chem Soc Chem Rev 2002;102:2227-02. e) Jensen WB. The lewis acid-base definitions: A status report. Am Chem Soc Chem Rev 1978;78:1-22.
5. Qiu R, Xu X, Peng L, Zhao Y, Li N, Yin S. Strong lewis acids of air-stable metallocene bis (Perfluorooctanesulfonate)s as high-efficiency catalysts for carbonyl-group transformation reactions. Chem Eur J 2012;18:6172-82.
6. Kantam ML, Aziz K, Likhar PR. Bis (cyclopentadienyl) zirconium dichloride for alkylation of heteroaromatics and synthesis of bis (indolyl) methanes. Catal Lett 2004;98:117-21.
7. Tamotsu T, Xi Z, Yasushi N, Hou S, Kasai K, Aoyagi K, et al. Convenient preparative method of ?? disubstituted cyclopentenone by zirconiumpromoted intramolecular coupling of alkyne EtMgBr or ethylene and (CO). Tetrahedron 1997;53:9123-34.
8. a) Jadhav J, Khanapure S, Salunkhe R, Rashinkar G. Organocatalytic synthesis of 2-substituted quinozolin-4(3H)-ones using dual activation strategy. Appl Organomet Chem 2013;27:486-8. b) Sonawane B, Rashinkar G, Sonawane K, Dhanavade M, Sonawane V, Patil S. Aerosil-supported ionic-liquid-phase (ASILP) mediated synthesis of 2-substituted benzimidazole derivatives as AChE inhibitors. Chem J 2018;20:5544-51.
9. Khanapure S, Jagadale M, Salunkhe R, Rashinkar G. Zirconocene dichloride catalyzed multi-component synthesis of 1-amidoalkyl-2-naphthols at ambient temperature. Res Chem Intermed 2016;42:2075 85.
10. Karhale S, Patil K, Bhenki C, Rashinkar G, Helavi V. Zirconocene catalyzed synthesis of 2-substituted benzimidazole derivatives Res Chem Intermed 2016;42:7257-68.
11. Kantam ML, Aziz K, Likhar PR. Applications of zirconium (IV) chloride in organic synthesis. Cat Commun 2006;7:484-7.
12. Denhez C, Medegan S, Helion F, Namy JL, Vasse JL Szymoniak J. Reduction of Cp2ZrCl2 with mischmetall: A new method for generating an efficient “Cp2Zr”. Equiv Org Lett 2006;8:2945-7.
13. Chouhan M, Sharma R, Nair VA. Cp2ZrCl2 induced reformatsky and barbier reactions on isatins: An efficient synthesis of 3 substituted 3 hydroxyindolin 2ones. Appl Organomet Chem 2011;25:470-5.
14. Li LH, Wallace TL, Richard KA, Tracey DE. Mechanism of antitumor action of pyrimidinones in the treatment of B16 melanoma and P388 leukemia. Cancer Res 1985;45:532-8.
15. Heber D, Heers C, Ravens U, Positive inotropic activity of 5-amino- 6- cyano- 1,3- dimethyl -1,2,3,4- tetrahydropyrido [2,3-d] pyrimidine-2,4-dione in cardiac muscle from guinea-pig and man. Part 6: Compounds with positive inotropic activity. Pharmazie 1993;48:537-41.
16. Grivsky EM, Lee S, Sigel CW, Duch DS, Nichol CA, Synthesis and antitumor activityof2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine J Med Chem 1980;23:327-9.
17. Broom AD, Shim JL, Anderson GL Pyrido[2,3-d]pyrimidines. IV. Synthetic studies leading to various oxopyrido[2,3-d] pyrimidines J Org Chem.1976;41:1095-9.
18. a) Balalaie S, Abdolmohammadi S, Bijanzadeh HR, Amani AM. Diammonium hydrogen phosphate as a versatile and efficient catalyst for the one-pot synthesis of pyrano [2,3-d] pyrimidinone derivatives in aqueous media. Mol Divers 2008;2008:85-91. b) Heravi MM, Ghods A, Bakhtiari K Derikvand F. Zn [(L)proline]2: An efficient catalystfor the synthesis of biologically active pyrano [2,3-d] pyrimidine derivatives. Synth Commun 2010;40:1927-31.
19. Bennett LR, Blankely CJ, Fleming RW, Smith RD, Tessman DK. Antihypertensive activity of 6-arylpyrido [2,3- d] pyrimidin-7-amine derivatives. J Med Chem 1981;24:382-9.
20. a) Ziarani GM, Faramarzi S, Asadi S, Badiei A, Bazl R, Amanlou M. Three-component synthesis of pyrano[2,3-d]-pyrimidine dione derivatives facilitated by sulfonic acid nanoporous silica (SBA-Pr-SO3H) and their docking and urease inhibitory activity. Daru J Pharm Sci 2013. Doi: 10.1186/2008-2231-21-3. b). Ghorab MM, Hassan AY. Synthesis and antibacterial properties of new dithienyl containing pyran, pyrano [2,3-b] pyridine, pyrano [2,3-d] pyrimidindine and pyridine derivatives. Phosphorus Sulfur Silicon Relat Elem 1998;141:251-61.
21. a) Shamroukh AH, Zaki ME, Morsy EM, Abdel-Motti FM, Abdel-Megeid FM. Synthesis of pyrazolo [4’,3’:5,6] pyrano [2,3-d]pyrimidine derivatives for antiviral evaluation. Arch Pharm 2007;340:236-43.
22. Tietze LF, Kettschau G, Padwa A. In Topics in Current Chemistry. Heidelberg: Springer; 1997. p. 189.
23. Sabry AE, Abdulla MM. Synthesis, reactions, and anti-inflammatory activity of heterocyclic systems fused to a thiophene moiety using citrazinic acid as synthon. Monatsh Chem 2007;138:699 700.
24. Sakuma Y, Hasegawa M, Kataoka K, Hoshina K, Yamazaki N, Kadota T, et al. 1, 10-phenanthroline derivatives. WO 91/05785 PCT. Int Appl 1989;115:1646.
25. Kitamura N, Onishi A. Synthesis of some novel pyrimido [1,6-a]pyrimidine derivatives 4, 8 and 10. Chem Abstr 1984;104:186439.
26. Bogdanowicz-Szwed K, Pa?asz A Synthesis of functionalized 3,4-dihydro-2H-pyrans by hetero- Dieis-Alder reaction of an enaminoketone. Enol Ethers Monatsh Chem 1995;126:1341-8.
27. Bhat AR, Shalla AH, Dongre RS Synthesis of new annulated pyrano [2,3-d]pyrimidine derivatives using organo catalyst (DABCO) in aqueous media. J Saudi Chem Soc 2014;21:305-10. b) Bhusnure OG, Vibhute YB, Giram PS, Vibhute AY, Gholve SB. Optimization of microwave assisted solvent-free synthesis of some schiff bases. Int J Pharm Pharm Sci 2015;7:124-8.
28. Jin TS, Liu LB, Tu SJ, Zhao Y, Li TS. A clean one-pot synthesis of 7-amino-5-aryl 6-cyano-1,5-dihydro- 2H-pyrano[2,3-d] pyrimidine-2,4(3H)-diones in aqueous media under ultrasonic irradiation. J Chem Res 2005;3:162-3.
29. Devi I, Kumar BS, Bhuyan PJ. A novel three-component one-pot synthesis of pyrano[2,3-d]pyrimidines and pyrido[2,3-d]pyrimidines using microwave heating in the solid state. Tetrahedron Lett 2003;44:8307-10.
30. Kurane R, Jadhav J, Khanapure S, Salunkhe R, Rashinkar G. Synergistic catalysis by an aerogel supported ionic liquid phase (ASILP) in the synthesis of 1,5-benzodiazepines. Green Chem 2013;15:1849-56.
31. Lee SC, Kim JH, Jeong SM, Kim DR, Ha JU, Nam KC, et al. Effect of far-infrared radiation on the antioxidant activity of rice hulls. J Agric Food Chem 2003;51:4400-3.
32. a) Benzie IF, Strain JJ. The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: The FRAP assay. Anal Biochem 1996;15:70-6. b) Banothu J, Rajitha G, Velpula R, Bavantul R. Brønsted acidic ionic liquid catalysis: An efficient and eco-friendly synthesis of novel fused pyrano pyrimidinones and their antimicrobial activity. J Chem Sci 2013;125:843-9. c) Sahu M, Siddiqui N. A review on biological importance of pyrimidines in the era. Int J Pharm Pharm Sci 2016;5:821. d) Patil RB, Sawant SD. Synthesis, docking studies and evaluation of antimicrobial and in vitro antiproliferative activity of 5Hchromoeno 4,3Dpyrimidin 2amine derivatives. Int J Pharm Pharm Sci 2015;7:3048. e) Nadaf NH, Parulekar RS, Patil RS, Gade TK, Momin AA, Waghmare SR, et al. Biofilm inhibition mechanism from extract of Hymenocallis littoralis leaves. J Ethnopharm 2018; 222:12132.
33. Dhanavade MJ, Jalkute CB, Ghosh JS, Sonawane KD. Study antimicrobial activity of lemon (Citrus lemon L.) peel extract. Br J Pharml Toxicol 2011;2:11922.
34. Sonawane KD, Dhanavade MJ. IGI Global Molecular Docking Technique to Understand EnzymeLigand Interactions. Methods and Algorithms for Molecular DockingBased Drug Design and Discovery. Iran: IGI. Global; 2016. p. 245.
35. Dhanavade MJ, Parulekar RS, Kamble SA, Sonawane KD. Molecular modeling approach to explore the role of cathepsin B from Hordeum vulgate in the degradation of A? peptides. Mol Biosyst 2016;12:162-8.
36. Parulekar RS, Barage SH, Jalkute CB, Dhanavade MJ, Fandilolu PM, Sonawane KD. Homology modeling, molecular docking and DNA binding studies of nucleotide excision repair UvrC protein from M. Tuberculosis. Protein J 2013;32:4676.
37. Sonawane KD, Parulekar RS, Malkar RS, Nimbalkar PR, Barrage SH, Jadhav DB. Homology modeling and molecular docking studies of ArnA protein from Erwinia amylovora: Role in polymyxin antibiotic resistance. J Plant Biochem Biotechnol 2015;24:42532.
38. Lin FY, Liu CI, Liu YL, Zhang Y, Wang K, Jeng W, et al. Mechanism of action and inhibition of dehydrosqualene synthase. Proc Natl Acad Sci 2010;107:2133742.
39. Duhovny D, Nussinov R, Wolfson HJ. Efficient unbound docking of rigid molecules. Comp Sci 2002;2452:185200.
40. Furubayashi M, Li L, Katabami A, Saito K, Umeno D. Directed evolution of squalene synthase for dehydrosqualene biosynthesis. FEBS Lett 2014;588:337581.
41. a) Mashkouri S, NaimiJamal MR. Mechanochemical solventfree and catalystfree onepot synthesis of pyrano [2,3d]pyrimidine2,4(1H,3H)diones with quantitative yields. Molecules 2009;14:474479. b) Slater JC. A simplification of the hartreefock method. Phys Rev 1951;81:38590.
42. Petersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, et al. Chimera a visualization system for exploratory research and analysis. J Comput Chem 2004;25:160512.
43. a) Sato Y, Mori M. Arylnaphthalene lignans through PdCatalyzed [2+2+2] cocyclization of arynes and diynes: Total synthesis. Angew Chem 2004;43:243640. b) Pandey OP, Sengupta SK, Tripathi CM. Reactions of Cp2MCl2 (M=Ti or Zr) with imineoxime ligands. Formation of metallacycles. Molecules 2005;10:6538.
44. Breinbauer R, Vetter IR, Waldmann H. From protein domains to drug candidatesnatural products as guiding principles in the design and synthesis of compound libraries. Angew Chem 2002;41:287990.
45. Breinbauer R, Vetter IR, Waldmann H. Small MoleculeProtein Interactions Heidelberg: Springer, Verlag; 2003.
139 Views | 183 Downloads
How to Cite
D SONAWANE, B., V. D. D SONAWANE, K. D SONAWANE, M. D. J DHANAVADE, C. B AWARE, S. K AWATE, and S. V PATIL. “Cp2ZrCl2: AN EFFICIENT CATALYST FOR MULTICOMPONENT SYNTHESIS OF CAROTENOID DEHYDROSQUALENE SYNTHASE INHIBITING PYRANO[2,3-d]PYRIMIDINEDIONES”. Asian Journal of Pharmaceutical and Clinical Research, Vol. 12, no. 2, Jan. 2019, pp. 280-8, doi:10.22159/ajpcr.2019.v12i2.26862.
Original Article(s)