Research on Chemical Intermediates

, Volume 39, Issue 5, pp 2157–2185 | Cite as

Inhibitory effect of some new uracil and thiouracil derivatives on cercarial penetration enzymes

  • O. A. Fathalla
  • M. E. Haiba
  • M. M. Anwar
  • Maha S. Almutairi
  • A. S. Maghraby
  • M. M. Bahgat


Some uracil- and thiouracil-5-sulfonohydrazide derivatives have been synthesized to be evaluated as antischistosomal agents. N-[2-(1,5-Dimethyl-3-oxo-2-phenylpyrazolin-4-yl)-4-oxo-1,3-thiazolidin-3-yl]-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-sulfonamide (3c) was formulated in jojoba oil and used to paint mice tails before infection with Schistosoma mansoni cercariae. Using Boc-Val-Leu-Gly-Arg-PNA, a specific substrate for trypsin-like serine proteinases, compound 3c inhibited cercarial serine protease activity with 50 % inhibition concentration (IC50) of 160 μg. Upon topical application on mice tails before infection with S. mansoni cercariae, it caused a 20 % reduction in worm burden compared with untreated infected mice. Using soluble crude cercarial antigen in enzyme-linked immunosorbent assay (ELISA), no significant changes were observed in the levels of immunoglobulin M (IgM) and IgG in sera from treated infected mice at 2, 4, and 6 weeks postinfection (WPI) compared with the level in sera from infected untreated mice. At 4 WPI, sera from treated infected mice showed significantly low (P < 0.05) IgM reactivity to crude soluble worm antigen compared with infected nontreated ones. IgG levels in sera from treated infected mice at 2 and 4 WPI were significantly lower (P < 0.05) than in sera from infected nontreated mice. At 6 WPI, the IgG response showed no significant differences in sera from both mice groups. Sera from treated infected mice at 2, 4, and 6 WPI had generally lower IgM reactivity to soluble egg antigen when compared with the level in sera from nontreated infected mice. At all time points postinfection, sera collected from treated infected mice showed significantly low IgG reactivity (P < 0.05) compared with infected nontreated mice.


Cercariae Cercarial serine protease IgM IgG 4-Oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-sulfonohydrazide Schistosoma mansoni 



This research project was supported by a grant from the research center of the center for female scientific and medical colleagues in King Saud University.


  1. 1.
    L.A.L. Quezada, J.H. McKerrow, Schistosome serine protease inhibitors: parasite defense or homeostasis? An. Acad. Bras. Cienc. 83, 663–672 (2011)CrossRefGoogle Scholar
  2. 2.
    A. Harder, Chemotherapeutic approaches to schistosomes: current knowledge and outlook. Parasitol. Res. 88, 395–397 (2002)Google Scholar
  3. 3.
    P. Steinmann, J. Keiser, R. Bos, M. Tanner, J. Utzinger, Schistosomiasis and water resources development: systematic review, meta-analysis and estimates of people at risk. Lancet Infect. Dis. 6, 411–425 (2006)CrossRefGoogle Scholar
  4. 4.
    M. Ismail, S. Botros, A. Metwally, S. William, A. Farghally, Resistance to praziquantel: direct evidence from Schistosoma mansoni isolated from Egyptian villagers. Am. J. Trop. Med. Hyg. 60, 932–935 (1999)Google Scholar
  5. 5.
    N.R. Bergquist, Schistosomiasis: from risk assessment to control. Trends Parasitol. 18, 309–314 (2002)CrossRefGoogle Scholar
  6. 6.
    M.A. Stirewalt, C.H. Dorsey, Schistosoma mansoni: cercarial penetration of host epidermis at the ultrastructural level. Exp. Parasitol. 35, 1–15 (1974)CrossRefGoogle Scholar
  7. 7.
    J.H. McKerrow, G. Newport, Z. Fishelson, Recent insights into the structure and function of a larval proteinase involved in host infection by a multicellular parasite. Proc. Soc. Exp. Biol. Med. 197, 119–124 (1991)Google Scholar
  8. 8.
    J. Pellegrino, Protection against human schistosome cercariae. Exp. Parasitol. 21, 112–131 (1967)CrossRefGoogle Scholar
  9. 9.
    R.R. Abu-Elyazeed, J.K. Podgore, N.S. Mansour, M.E. Kilpatrick, Field trial of 1 % niclosamide as a topical antipenetrant to Schistosoma mansoni cercariae. Am. J. Trop. Med. Hyg. 49, 403–409 (1993)Google Scholar
  10. 10.
    J.K. Podgore, R.R. Abu-Elyazeed, N.S. Mansour, F.G. Youssef, R.G. Hibbs, J.A. Gere, Evaluation of a twice-a week application of 1 % niclosamide lotion in preventing Schistosoma haematobium reinfection. Am. J. Trop. Med. Hyg. 51, 875–879 (1994)Google Scholar
  11. 11.
    M. Bahgat, K. Francklow, M.J. Doenhoff, Y.L. Li, R.M. Ramzy, C. Kirsten, A. Ruppel, Infection induces antibodies against the cercarial secretions, but not against the cercarial elastases of Schistosoma mansoni, Schistosoma haematobium, Schistosoma japonicum, and Trichobilharzia ocellata. Parasite Immunol. 23, 557–565 (2001)CrossRefGoogle Scholar
  12. 12.
    M. Bahgat, A.S. Maghraby, M.E. Heiba, A. Ruppe, O.A. Fathalla, Synthesis of new 4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine derivatives with an incorporated thiazolidinone moiety and testing their possible serine protease and cercarial elastase inhibitory effects with a possible prospective to block penetration of Schistosoma mansoni cercariae into the mice skin. Arch Pharm Res. 28, 1002–1012 (2005)CrossRefGoogle Scholar
  13. 13.
    A. Ruppel, K. Chlichlia, M. Bahgat, Invasion by schistosome cercariae: neglected aspects in Schistosoma japonicum. Trends Parasitol. 20, 397–400 (2004)CrossRefGoogle Scholar
  14. 14.
    H. Mitsuya (ed.), Anti-HIV nucleosides: past, present and future (Chapman and Hall, New York, 1997)Google Scholar
  15. 15.
    F. Ahmad Eweas, S. A. Swelam, O.A. Fathalla, N.M. Fawzy, Sh.I. Abdel-Moez, Synthesis, anti-microbial evaluation, and molecular modeling of new pyrazolo[3,4-d]pyrimidine derivatives. Med. Chem. Res. (2011). doi: 10.1007/s00044-011-9911
  16. 16.
    T.S. Chitre, K.G. Bothara, S.M. Patil, K.D. Asgaonkar, S. Nagappa, M.K. Kathiravan, Design, synthesis, docking and anti-mycobacterial activity of some novel thiouracil derivatives as thymidine monophoshate kinase (TMPKmt) inhibitors. Int. J. Res. Pharm. Biomed. Sci. 2, 616–623 (2011)Google Scholar
  17. 17.
    N.R. Mohamed, M.M. El-saidi, Y.M. Ali, M.H. Elnagdi, Utility of 6-amino-2-thiouracil as precursors for the synthesis of pyrido[2,3-d]pyrimidines and their in vitro and in vivo biological evaluation. Sci. Pharm. 75, 9–28 (2007)CrossRefGoogle Scholar
  18. 18.
    V. Alagarsamy, S. Vijayakumar, R.V. Solomon, Synthesis of 2-mercapto3-substituted-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-ones as new analgesic, anti-inflammatory agents. Biomed. Pharmacother. 61, 285–291 (2007)CrossRefGoogle Scholar
  19. 19.
    E. Nicola, M. Kirchner, F. Caussade, A. Cloarec, In vivo pharmacological characterization of UP 269–6, a novel non-peptide angiotensin II receptor antagonist. Eur. J. Med. Chem. 284, 157–170 (1995)Google Scholar
  20. 20.
    O.A. Fathalla, M.A.H. Ismail, M.M. Anwar, K. A.M. Abouzid, A.A. K. Ramadan, Novel 2-thiopyrimidine derivatives as CDK2 inhibitors: molecular modeling, synthesis, and anti-tumor activity evaluation. Med. Chem. Res. (2012). doi: 10.1007/s00044-012-0051-9
  21. 21.
    O.A. Fathalla, H.S.M. Gad, A.S. Maghraby, Synthesis of some new uracil-5-sulphonamide-p-phenyl derivatives and their effect on Biomphalaria alexandrina snail’s nucleoproteins. Arch. Pharm. Res. 23, 128–138 (2000)CrossRefGoogle Scholar
  22. 22.
    O.A. Fathalla, M.E. Haiba, A.S. Maghraby, Synthesis of new uracil-5-sulfonamide derivatives and immuno-stimulatory effect of a chemically modified hemolymph of bio-mphalaia alexandrina on Schistosoma mansoni infected mice. Arch. Pharm. Res. 26, 358–366 (2003)CrossRefGoogle Scholar
  23. 23.
    O.A. Fathalla, A.S. Maghraby, Some pyrimidine-2,4 (1H,3H)-dione derivatives: immunization of mice with Biomphalaria alexandrina snail’s nuceoproteines treated with some pyrimidine-2,4(1H,3H)-dione derivatives and prazaquantel induced mesentric lymph nodes and splenic lymphocytes. Bull. Fac. Pharm. Cairo Univ. 43, 183–193 (2005)Google Scholar
  24. 24.
    O.A. Fathalla, Synthesis of some new thiouracil derivatives with expected biological activity. Ind. J. Chem. 40B, 37–42 (2001)Google Scholar
  25. 25.
    L. Oliver, M.A. Stirewalt, An effective method for the exposure of mice to cercariae of Schistosoma mansoni. J. Parasitol. 38, 1923 (1952)Google Scholar
  26. 26.
    A.I. Vogel, Text book of organic chemistry, 3rd edn. (Lowe and Brydone, London, 1972)Google Scholar
  27. 27.
    R.H. Duvall, W.B. Dewitt, An improved perfusion technique for recovering adult Schistosomes from laboratory animals. Am. J. Trop. Med. Hyg. 16, 483–486 (1967)Google Scholar
  28. 28.
    M. Bahgat, A. Ruppel, Biochemical comparison of the serine protease (elastase) activities in cercarial secretions from Trichobilharzia ocellata and Schistosoma mansoni. Parasitol. Res. 288, 495–500 (2002)Google Scholar
  29. 29.
    W. He, B. Hanney, M.R. Myers, A.P. Spada, K. Brown, D. Colussi, V. Chu, Non-benzamidine compounds as selective factor Xa inhibitors. Bioorg. Med. Chem. Lett. 10, 1737–1739 (2000)CrossRefGoogle Scholar
  30. 30.
    Cruthers et al., Topical prophylaxis against schistosomal infections, United States Patent 4659738–4173632. Nov 1979Google Scholar
  31. 31.
    B. Salafsk, A.C. Fusco, L.H. Li, J. Mueller, B. Ellenberger, Schistosoma mansoni: experimental chemoprophylaxis in mice using oral anti-penetration agents. Parasitology 69, 263–271 (1989)Google Scholar
  32. 32.
    E. Cooper, A. Iqbal, A. Bartlett, C. Marriott, P.J. Whitfield, M.B.A. Brown, Comparison of topical formulations for the prevention of human schistosomiasis. J. Pharm. Pharmacol. 56, 957–962 (2004)CrossRefGoogle Scholar
  33. 33.
    G. Rai, A.A. Sayed, W.A. Lea, H.F. Luecke, H. Chakrapani, S.P. Chakrapani, A. Jadhav, W. Leister, M. Shen, J. Inglese, C.P. Austin, L. Keefer, S.J. Elias, A. Simeonov, D.J. Maloney, D.L. Williams, C.J. Thomas, Structure mechanism insights and the role of nitric oxide donation guide the development of oxadiazole-2-oxides as therapeutic agents against schistosomiasis. J. Med. Chem. 52, 6474–6483 (2009)CrossRefGoogle Scholar
  34. 34.
    M. Bahgat, M.N. Aboul-Enein, A.A. El Azzouny, A.S. Maghraby, A. Ruppel, W.M.A. Soliman, Cyclohexanecarboxamide derivatives with inhibitory effects on Schistosoma mansoni cercarial serine protease and penetration of mice skin by the parasite. Acta Pol. Pharm. 66, 333–340 (2009)Google Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • O. A. Fathalla
    • 1
  • M. E. Haiba
    • 1
    • 2
  • M. M. Anwar
    • 1
  • Maha S. Almutairi
    • 2
  • A. S. Maghraby
    • 1
    • 3
  • M. M. Bahgat
    • 1
    • 3
  1. 1.Department of Therapeutical ChemistryNational Research CentreCairoEgypt
  2. 2.Department of Pharmaceutical Chemistry, College of PharmacyKing Saud UniversityRiyadhSaudi Arabia
  3. 3.Laboratory of Immunology and Infectious Diseases, the Center of Excellence for Advanced SciencesNational Research CenterCairoEgypt

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