15Nov 2019


  • Laboratoire de Chimie Organique Physique et de Synthese (LaCOPS), Departement de Chimie, Faculte des Sciences et Techniques (FAST), Universite d Abomey-Calavi, 01 BP 4521 Cotonou, Benin
  • Laboratoire de Chimie Organique Pharmaceutique, Ecole de Pharmacie, Faculte des Sciences de la Sante, Universite d Abomey - Calavi, Campus du Champ de Foire, 01 BP 188, Cotonou, Benin
  • Louvain Drug Research Institute (LDRI), School of Pharmacy, Universite Catholique de Louvain, B1 7203 Avenue Emmanuel Mounier 72, B-1200 Brussels, Belgique
  • Department of Biology and Center for Computational and Integrative Biology, Rutgers University, Camden, NJ 08102, USA
Crossref Cited-by Linking logo
  • Abstract
  • Keywords
  • References
  • Cite This Article as
  • Corresponding Author

Traditionally, small molecules have been a reliable source for discovering novel biologically active compounds because these molecules are easily synthesized and their smooth structural optimization would usually lead to a feasible candidate compound. Here, some thiosemicarbazones, N(4)-methyl and N(4)-phenyl-3-thiosemicarbazones were synthesized in good yield (52-84%), characterized and then their anti-parasitic activity were evaluated. The structure and lipophilic-activity relationships of compounds were particularly studied. Among them, some products exhibited trypanocidal activity with their half inhibitory concentration (IC50 ? 10 micromolar ??M?) especially compounds L1-3, D2, B3, C3, D1 (from 2 to 8.73 ?M). Other showed moderate antitrypanosomal activity with their IC50 between 12 to 87 ?M (L4, C2, C1, B2) while certain showed little activity (IC50 ? 100?M). Some active products turned out quick selective on the parasite with their selectivity index greater than to unit (SI ? 1). Several factors including lipophilicity, steric and electronic effects of the substituents have played a vital role in this activity. The elongation of the carbon chain of the carbonyl, the substitution on a phenyl radical, the fixing of a methyl or phenyl on the N(4) nitrogen atom induced significantly the increased trypanocidal activity of compounds. This is the case specifically of N(4)-methyl and especially of N(4)-phenyl-substituted thiosemicarbazones. Such compounds could be able to have applications in the treatment of parasitic diseases

  1. Soates, O.A.R., Echevarria, A., Bellieny, S.S.M., Pinho, T.R., de Leo, M.M.R., Seguins, A.W., Machado, M.G., Canto-Cavalheiro, M.M., Leon, L.L. (2011). Evaluation of thiosemicarbazones and semicarbazones as potential agents anti-Trypanosoma cruzi. Experimental Parasitology. 129(4): 381-387.
  2. Rogolino, D., Bacchi, A., De Luca, L., Rispoli G, Sechi, M., Stevaert, A., Naesens, L., Carcelli, M. (2015). Investigation of the salicylaldehyde thiosemicarbazone scaffold for inhibition of influenza virus PA endonuclease. Journal of Biologiocal Inorganic Chemistry. 20: 1109?1121. doi: 10.1007/s00775-015-1292-0.
  3. B?scher, P., Cecchi, G., Jamonneau, V., Priotto, G. (2017). Human African trypanosomiasis. Lancet. 390: 2397-409.
  4. Zani, C., Bisceglie, F., Restivo, F.M., Feretti, D., Pioli, M., Degola, F., Montalbano, S., Galati, S., Pelosi, G., Viola, G.V.C., Carcelli, M., Rogolino. D., Ceretti, E., Buschini, A. (2017). A new approach using a battery of assays to evaluate the efficacy of thiosemicarbazone derivatives as antifungal and anti-mycotoxigenic agents and their cytotoxic and genotoxic activity. Food and Chemical Toxicology. 105: 498-505. doi: 10.1016/j.fct.2017.05.008.
  5. Du, X., Guo, C., Hansell, E., Doyle, S.P., Caffrey, C.R., Holler, T.P., McKerrow, J.H., Cohen, F.E. (2002). Synthesis and Structure-Activity Relationship Study of Potent Trypanocidal thiosemicarbazone Inhibitors of the Trypanosomal Cysteine Protease Cruzain. Journal of Medicinal Chemistry. 45: 2695-2707.
  6. Beraldo, H. and Gambino, D. (2004) Semicarbazones and thiosemicarbazones: their wide pharmacological profile and clinical applications. Qu?mica Nova. 27: 461?471.
  7. Fujii, N., Mallari, J.P., Hansell, E.J., Mackey, Z., Doyle, P., Zhou, Y.M., Gut, J., Rosenthal, P.J., McKerrow, J.H., Guy, R.K. (2005). Discovery of potent thiosemicabazones inhibitors of rhodesain and cruzain. Bioorganic and Medicinal Chemistry. 15(1): 121-123.
  8. Jeremy, P.M., Anang, S., Aaron, K., Conor, R.C., Michele, C., Fangyi, Z., James H.M., Guy, R.K. (2008). Discovery of trypanocidal thiosemicarbazone inhibitors of rhodesain and TbcatB. Bioorganic and Medicinal Chemistry Letters. 18(9): 2883-2885.
  9. Simarro, P.P., Cecchi, G., Franco, J.R., Paone, M., Diarra, A., Ruiz-Postigo, J.A., F?vre, M.E., Mattioli, C.R., Jannin, G.J. (2012). Estimating and mapping the population at risk of Sleeping Sickness. PLoS Neglected Tropical Diseases. 6(10)?: e1859. doi: 10.1371/journal.pntd.0001859
  10. Grant, C., Anderson, N. and Machila, N. (2015). Stakeholder Narratives on Trypanosomiasis, Their Effect on Policy and the Scope for One Health. PLoS Neglected Tropical Diseases. 9(12): e0004241. doi:?1371/journal.pntd.0004241
  11. Amer, S., Ryu, O., Tada, C., Fukuda, Y., Inoue, N. et Nakai, Y. (2011). Molecular identification and phylogenetic analysis of Trypanosoma evansi from dromedary camels (Camelus dromedarius) in Egypt: a pilot study. Acta Tropica. 117(1): 39-46. doi: 10.1016/j.actatropica.2010.09.010.
  12. Cox, A.P., Tosas, O., Tilley, A., Picozzi, K., Coleman, P., Hide, G. & Welburn, S.C. ( 2010). Constraints to estimating the prevalence of trypanosome infections in East African zebu cattle. Parasite Vectors. 3: 82.
  13. Baltz, T., Baltz, D., Giroud, C., Crockett, J. (1985). Cultivation in a semi defined medium of animal infective forms of Trypanosoma brucei, equiperdum, T. evansi, T. rhodhesiense et T. gambiense. EMBO Journal. 4(5): 1273-1277.
  14. R?z, B., Iten, M., Grether-B?hler, Y., Kaminsky, R., Brun, R. (1997). The Alamar BlueTM assay to determine drugs sensitivity of African trypanosomes (Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense) in vitro. Acta Tropica. 68: 139-147.
  15. Sleet, R.B., Brendel, K. (1983). Improved methods for harvesting and counting synchronous populations of Artemia nauplii for use in developmental toxicology. Ecotoxicology and Environmental Safety. 7: 435-446.
  16. Abbott, W.A. (1925). A method of computing the effectiveness of an insecticide. Journal of Economic and Entomology 18: 265.
  17. Hafner, E., Heiner, E., Noack, E. (1977). Mathematical analysis of concentration-response relationships. Arzneimittel-Forschung / Drug Research. 27: 1871-1873.
  18. Lipinski, C.A., Lombardo, F., Dominy, B.W., Feeney, P.J. (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews. 23: 3-25.
  19. Lipinski, C.A., Lombardo, F., Dominy, W.B., Feeney, J.P. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews. 46: 3-26.
  20. Greenbaum, D.C., Mache, Z., Hansell, E., Doyle, P., Gut, J., Caffrrey, C.R., Lehrman, J., Rosenthal, P.J., McKerrow, J.H., Chibale, K. (2004). Synthesis and structure activity relationships of parasiticidal thiosemicarbzone cysteine protease inhibitors against P. falciparum, T. brucei and T. cruzi. Journal of Medicinal Chemistry. 47(12):3212-3219.
  21. Pandeya, S.N., Yogeeswari, P., Sausville, E.A., Mauger, A.B., Narayanan, V.L. (2000). Synthesis and antitumour activity of some aryl semicarbazones. Scientia Pharmaceutica. 68: 369-377.
  22. P?rez-Rebolledo, A., Teixeira, L.R., Batista, A.A., Mangrich, A.S., Aguirre, G., Cerecetto, H., Gonzalez, M., Hernandez, P., Ferreira, A.M., Speziali, N.L., Beraldo, H. (2008). 4-nitroacetophenone derived thiosemicarbazones and their copper (II) complexes with significant in vitro antitrypanosomal activity. European Journal of Medicinal Chemistry. 43(5): 939-948.
  23. Santos, P.L.P., Pinto, G.B., Takahashi, J.A., Silva, L.G.F., Boaventura, M.A.D. (2003). Biological screening of Annonaceous Brazilian medicinal plants using Artemia salina (Brine shrimp test). Phytomedicine. 10(2-3): 209-212.
  24. Graminha, A.E., Batista, A.A., Louro, S.R.W., Ziolli, R.L., Teixeira, L.R., Beraldo, H. (2008). 2-Pyridinoformamide-derived thiosemicarbazones and their iron(III) complexes : potential antineoplastic activity. Polyhedron. 27: 547?551.
  25. Pelka, M., Danzl, C., Distler, W., Petschelt, A. (2000). A new screening test for toxicity testing of dental materials. Journal of Dentistry. 28(5): 341-345.
  26. Carballo, J.L., Hern?ndez-Inda, Z.L., Perez, P., Garcıa-Gravalos, D.C. (2002). A comparison between two brine shrimp assays to detect in vitro cytotoxicity in marine natural products. BMC Biotechnology. 2: 17. doi:10.1186/1472-6750-2-17
  27. Tiuman, T.S., Ueda-Nakamura, T., Garcia Cortez, D.A., Dias Filho, B.P., Morgado-Diaz, J.A., de Souza, W., Nakamura, C.V. (2005). Antileishmanial activity of Parthenolide, a sesquiterpene lactone isolated from Tanacetum parthenium. Antimicrobial Agents chemother. 492: 176-182.

[Glinma Bienvenu, Medegan Sedami, Yayi Eleonore, Agnimonhan F. Hyacinthe, Kpoviessi D.S. Salome, Quetin-leclercq Joelle, Accrombessi C. Georges, Kotchoni O. Simeon, Poupaert H. Jacques and Gbaguidi A. Fernand (2019); LIPOPHILIC AND STRUCTURE ACTIVITY RELATIONSHIPS STUDY OF THIOSEMICARBAZONES AND DERIVATIVES Int. J. of Adv. Res. 7 (Nov). 29-40] (ISSN 2320-5407). www.journalijar.com

GLINMA Bienvenu
Laboratoire de Chimie Organique Physique et de Synthèse, Faculté des Sciences et Techniques, Faculté des Sciences et Techniques, Faculté des Sciences et Techniques, Université d'Abomey-Calavi, BENIN


Article DOI: 10.21474/IJAR01/9971       DOI URL: http://dx.doi.org/10.21474/IJAR01/9971

Share this article