Abstract
The present work involves the synthesis of previously unknown 5-(isoindole-1,3-dione) pyrimidinones by [4 + 2] cycloaddition reactions of functionalized 1,3-diazabuta-1,3-dienes with phthalimidoketene, generated in situ from phthaloylglycine, tosyl chloride, and triethylamine. The 5-(isoindole-1,3-dione)-pyrimidinones have been screened in vivo for their anticonvulsant activities using MES and PTZ methods. A comparative study for in vivo anticonvulsant activities of these functionalized pyrimidinones with a variety of substitutions at different positions was also conducted. 2-(4-Dimethylamino-6-oxo-1,2-diphenyl-1,6-dihydro-pyrimidin-5-yl)-isoindole-1,3-dione has shown the maximum anticonvulsant activities at 100 mg/kg test dose using MES and PTZ tests.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Brands M, Grande YC, Endermann R, Gahlmann R, Krüger J, Raddatz S (2003) Pyrimidinone antibiotics—heterocyclic analogues with improved antibacterial spectrum. Biol Med Chem Lett 13:2641–2645
Brown DJ (1984) Pyrimidines and their benzoderivatives. In: Katritzky AR, Rees CW (eds) Comprehensive heterocyclic chemistry, vol 3. Pergamon Press, Oxford, pp 57–155
Edrees MM, Farghaly TA, El-Hag FAA, Abdalla MM (2010) Antimicrobial, antitumor and 5α-reductase inhibitor activities of some hydrazonoyl substituted pyrimidinones. Eur J Med Chem 45:5702–5707
Fu JM, Ennis M, Hoffman R, Verhoest P, Mickelson J, Corbett J (2005) Substituted pyrimidinones and pyrimidinthiones. US patent US 20050143403 A1 Filled 20 Apr 2004 Issued 30 Jun 2005
Giles FJ (2002) Troxacitabine-based therapy of refractory leukemia. Expert Rev Anticancer Ther 2:261–266
Goel RK, Singh D, Lagunin A, Poroikov V (2011) PASS-assisted exploration of new therapeutic potential of natural products. Med Chem Res 20:1509–1514
Hopkins AL, Ren J, Tanaka H, Baba M, Okamato M, Stuart DI, Stammers DK (1999) Design of MKC-442 (emivirine) analogues with improved activity against drug-resistant HIV mutants. J Med Chem 42:4500–4505
Jayakumar S, Ishar MPS, Mahajan MP (2002) Recent advances in synthetic applications of azadienes. Tetrahedron 58:379–471
Kaur M, Goel RK (2011) Anti-convulsant activity of Boerhaavia diffusa: plausible role of calcium channel antagonism. Evid Complement Altern Med 2011:1–7. doi:10.1093/ecam/nep192
Knapp S (1995) Synthesis of complex nucleoside antibiotics. Chem Rev 95:859–1876
Loscher W, Schmidt D (2011) Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma. Epilepsia 52:657–678
Petricci E, Mugnaini C, Radi M, Togninelli A, Bernardini C, Manetti F, Parlato MC, Renzulli ML, Alongi M, Falciani C, Corelli F, Botta M (2006) Towards new methodologies for the synthesis of biologically interesting 6-substituted pyrimidines and 4(3H)-pyrimidinones. Arkivoc 8:452–478 (and reference cited therein)
Poroikov VV, Filimonov DA, Ihlenfeldt WD, Gloriozova TA, Lagunin AA, Borodina YV, Stepanchikova AV, Nicklaus MC (2003) PASS biological activity spectrum predictions in the enhanced open NCI database browser. J Chem Inf Comput Sci 43:228–236
Sharma AK, Mahajan MP (1997) Synthesis and [4+2] cycloaddition reactions of 4-(N-allyl-N-aryl)amino-1,3-diaza-1,3-butadienes with vinyl-, isopropenyl- and chloroketenes: entry to novel pyrimidinone/fused pyrimidinone derivatives. Tetrahedron 53:3841
Singh D, Goel RK (2009) Anticonvulsant effect of Ficus religiosa: role of serotonergic pathways. J Ethnopharmacol 123:330–334
Swinyard EA, Brown WC, Goodman LS (1952) Comparative assays of antiepileptic drugs in mice and rats. J Pharmacol Exp Ther 106:319–330
Tanaka H, Takashima H, Ubasawa M, Sekiya K, Nitta I, Baba M, Shigeta S, Walker RT, De Clercq E, Miyasaka T (1992) Structure-activity relationships of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine analogs: effect of substitutions at the C-6 phenyl ring and at the C-5 position on anti-HIV-1 activity. J Med Chem 35:337
Ulloora S, Shabaraya R, Ranganathan R, Adhikari AV (2013a) Synthesis, anticonvulsant and anti-inflammatory studies of new 1,4-dihydropyridin-4-yl-phenoxyacetohydrazones. Eur J Med Chem 70:341–349
Ulloora S, Shabaraya R, Aamir S, Adhikari AV (2013b) New imidazo[1,2-a]pyridines carrying active pharmacophores: synthesis and anticonvulsant studies. Bio Med Chem Lett 23:1502–1506
Zakharova VM, Serpi M, Krylov IS, Peterson LW, Breitenbach JM, Borysko KZ, Drach JC, Collins M, Hilfinger JM, Kashemirov BA, McKenna CE (2011) Tyrosine-based 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine and - adenine ((S)-HPMPC and (S)-HPMPA) prodrugs: synthesis, stability, antiviral activity and in vivo transport studies. J Med Chem 54:5680–5693
Acknowledgments
The authors are thankful to the Department of RIC, Punjab Technical University, Kapurthala-144601, Punjab, for providing the research facilities. R.S. and C.M. are especially thankful to Amritsar College of Engineering and Technology and Rayat Bahra College of Pharmacy for the research support. The authors are thankful to Sphaera Pharma for NMR and other instrumentation support. The authors acknowledge the role of PASS online computer program for the generation of biological activity spectrum.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sharma, R., Gawande, D.Y., Mohan, C. et al. Synthesis and anticonvulsant activities of functionalized 5-(isoindole-1,3-dione)-pyrimidinones. Med Chem Res 25, 1420–1424 (2016). https://doi.org/10.1007/s00044-016-1580-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00044-016-1580-4