Document Type: Short communication


1 Institute of Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Johann Wolfgang Goethe-University Frankfurt, Max-von-Laue-Straße 7, D-60438 Frankfurt am Main, Germany

2 Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4051 Basel, Switzerland


A set of conformationally restricted analogues of the natural product primin were synthesized as potential antiprotozoal agents. The synthesis utilizes quinone C-H functionalization methods to enable an efficient and easy access to primin analogues. The antiprotozoal activities of this series were evaluated in a panel of parasites and compared with the natural product primin. For all synthesized primin analogues a potent in vitro activity was found against the pathogen Trypanosoma brucei rhodesiense (IC50 < 0.05 µg/mL). The observed antiprotozoal activity is not related to production of reactive oxygen species (ROS). Initial results of the in vivo experiments with a T. b. rhodesiense rodent animal model of the human disease were also reported. Intraperitoneal injection administration of compound 7 resulted in complete clearance of T. b. rhodesiense in tested rodent animals 24 hours after the last treatment. Our results show that the primin scaffold represents a new scaffold for further development of potent inhibitors of Trypanosoma brucei rhodesiense.

Graphical Abstract


Main Subjects

References and Notes

  1. H. Schildknecht, I. Bayer, Schmidt Zeitschrift für Naturforsch. Part B-Chemie Biochem. Biophys. Biol. und verwandten Gebieten1967, B22 (1), 36.
  2. G.Guella, I. Mancini, F. Pietra, Helv. Chim. Acta1987, 70 (3), 621.
  3. P. Moosophon, S. Kanokmedhakul, K. Kanokmedhakul, J. Nat. Prod.2011, 74 (10), 2216.
  4. Y. Hong, S. Sengupta, W. Hur, T. Sim,J. Med. Chem.2015, 58 (9), 3739.
  5. I.-K. Lee, B.-S. Yun, S.-M. Cho, W.-G. Kim, J.P. Kim, I.-J. Ryoo, H. Koshino, I.D. Yoo, J. Nat. Prod.1996, 59 (11), 1090.
  6. A. A. L. Gunatilaka, J. M. Berger, R. Evans, J. S. Miller, J. H. Wisse, K. M. Neddermann, I. Bursuker, D. G. I. Kingston, J. Nat. Prod.2001, 64 (1), 2.
  7. D. Tasdemir, R. Brun, V. Yardley, S. G. Franzblau, P. Rüedi, Chem. Biodivers.2006, 3 (11), 1230.
  8. M.S. Butler, Nat. Prod. Rep.2005, 22 (2), 162.
  9. D. J. Newman, G. M. Cragg, J. Nat. Prod.2016, 79 (3), 629.
  10. Y. Hata,M. Raith, S. Ebrahimi, S. Zimmermann, T. Mokoka, D. Naidoo, G. Fouche, V. Maharaj, M. Kaiser, R. Brun, et al. Planta Med.2013, 79 (06), 492.
  11. A. Bhattacharya, T. Kaur, K. Ganesh, Synthesis (Stuttg).2010, 2010 (07), 1141.
  12. A. Gunatilaka, J. Berger, R. Evans, J. Miller, J. Wisse, K. Neddermann, I. Bursuker, D. Kingston,J. Nat. Prod.2001, 64 (1), 2.
  13. L. W. Bieber, A. de Andrade Chiappeta, M. A. de Moraes e Souza, M. Generino, P. R. Neto, J. Nat. Prod.1990, 53 (3), 706.
  14. H. Nasiri, J. Ferner, C. Tukek, S. Krishnathas, H. Schwalbe,Tetrahedron Lett.2015, 56 (17), 2231.
  15. J. M. Saa, J. Morey, C. Rubido, C. J. Org. Chem.1986, 51 (23), 4471.
  16. T. T. Wager, X. Hou, P. R. Verhoest, A. Villalobos, ACS Chem. Neurosci.2010, 1 (6), 435.
  17. F. Fonseca-Silva, J. D. F. Inacio, M. M. Canto-Cavalheiro,  E. E. Almeida-Amaral, J. Nat. Prod.2013, 76 (8), 1505.
  18. F. Fonseca-Silva, M. M. Canto-Cavalheiro, R. F. S. Menna-Barreto, E. E. Almeida-Amaral, J. Nat. Prod.2015, 78 (4), 880.
  19. J. B. Baell, J. Nat. Prod.2016, 79 (3), 616.
  20. H. R. Nasiri, P. Mracek, S. K. Grimm, J. Gastaldello,  A. Kolodzik, D. Ullmann, Medchemcomm2017, 8 (6), 1220.
  21. H. Nasiri, K. Hohmann, M. Hatemler, A. Plodek, F. Bracher, H. Schwalbe, Med. Chem. Res.2017, 26 (6), 1170.
  22. Caution: Primin (1) and its analogues are skin sensitizers. The contact with skin should be avoided. 2-Methoxy-1,4- benzoquinoe and quinone (12) were commercially available.General synthesis procedure: This C-H direct functionalization of quinones was first described by Baran as a scalabe reaction, which procceds at room temperature in an open flask.230.5g (3.6mmol) 2-methoxy-1,4-benzoquinone and the corresponding boronic acids (1eq. 3.6mmol) were dissolved in dichloromethane (DCM). To this reaction mixture 0.12g (0.72mmol, 0.2 eq) Silver nitrate in 18mL water and 1.9g (7.2 mmol, 2eq) potassium persulfate in 11mL DCM was added. The reaction mixture was stirred at room temperature for 18h.For the workup, 20mL DCM was added and the organic phase washed with 5% hydrogen carbonate solution. The product was purified on silica chromatography using hexane:ethylacetate as eluent.Compound 7:1H – NMR: (400 MHz, CDCl3): δ [ppm] = 6.42 (s, 1H, C[3]), 5.85 (s, 1H, C[5]), 3.71 (s, 3H, C[7]), 3.02 (q, 1H, C[1‘]), 1.90 (m, 4H, C[2‘], C[5‘]), 1.65 (m, 2H, C[3‘]), 1.36 (m, 2H, C[4‘])13C – NMR: (400 MHz, CDCl3): δ [ppm] = 187.6 [C], 182.8 [C], 158.5 [C], 154.3 [C], 128.3 [CH], 108.1 [CH], 56.2 [CH3], 38.7 [CH], 32.3 [2x CH2], 25.3 [2x CH2]Compound 8:1H – NMR: (400 MHz, CDCl3): δ [ppm] = 6.40 (s, 1H, C[3]), 5.79 (s, 1H, C[6]), 3.75 (s, 3H, C[7]),  3.01 (q, 3J = 7.52 Hz, 1H, C[1‘]), 1.90 (m, 4H, C[2‘], C[5‘]), 1.65 (m, 2H, C[3‘]), 1.36 (m, 2H, C[4‘])13C – NMR: (400 MHz, CDCl3): δ [ppm] = 188.1 [C], 182.3 [C], 159.3 [C], 151.3 [C], 130.7 [CH], 107.0 [CH], 56.4 [CH3], 38.7 [CH], 32.1 [2x CH2], 25.1 [2x CH2]Compound 9:1H-NMR: (500 MHz, CDCl3): δ [ppm] = 6.36 (s, 1H, C[3]), 5.79 (s, 1H, C[5]), 3.74 (s, 3H, C[7]), 2.65 (t, 3J = 11.89, 1H, C[1’]), 1.72 (m, 4H, C[2’], C[6’]), 1.35 (m, 4H, C[3’], C[5’]), 0.77 (m, 2H, C[4’])13C-NMR: (500 MHz, CDCl3): δ [ppm] = 188.06 [C], 181.80 [C], 158.80 [C], 151.96 [CH], 131.29 [C], 106.84 [CH], 58.18 [CH3], 36.09 [CH], 32.02 [2x CH2], 29.84 [2x CH2], 26.34 [CH2]Compound 10:1H-NMR: (500 MHz, CDCl3): δ [ppm] = 6.36 (s, 1H, C[3]), 5.85 (s, 1H, C[6]), 3.74 (s, 3H, C[7]), 2.64 (t, 3J = 12.16, 1H, C[1’]), 1.72 (m, 4H, C[2’], C[6’]), 1.35 (m, 4H, C[3’], C[5’]), 1.09 (m, 2H, C[4’])13C-NMR: (500 MHz, CDCl3): δ [ppm] = 187.18 [C], 182.67 [C], 158.22 [C], 154.72 [CH], 128.67 [C], 107.86 [CH], 55.89 [CH3], 36.10 [CH], 32.45 [2x CH2], 27.07 [2x CH2], 26.20 [CH2]
  23. Biological assaysIn vitro activity. The in vitro activity of the compounds were determinded against T.b.rhodesiense (bloodstream trypomastigotes, STIB 900 strain), T.cruzi (amastigotes, Tulahuen C4 strain), L.donovani (axenic grown amastigotes, MHOM-ET-67/L82 strain), P. falciparum (intra-erythrocytic forms, NF54 strain), and cytotoxicity against mammalian cells (L6 cells, rat-skeletal myoblasts) as previously described.24 In vivo efficacy studies: In vivo experiments were performed in T.b. rhodesiense (STIB900) infected mice as previously described.25 In vivo efficacy studies in mice were conducted according to the rules and regulations for the protection of animal rights (“Tierschutzverordnung”) of the Swiss “Bundesamt für Veterinärwesen”. They were approved by the veterinary office of Canton Basel-Stadt, Switzerland.
  24. Y. Fujiwara, V. Domingo, I. B. Seiple, R. Gianatassio, M. Del Bel, P.S. Baran, J.Am.Chem.Soc.2011, 133, 3292.
  25. I. Orhan, B. Şener, M. Kaiser, R. Brun, D. Tasdemir, Mar. Drugs2010, 8 (1), 47.
  26. M. Kaiser, M.A. Bray, M. Cal, B. Bourdin Trunz, E. Torreele, R. Brun, Antimicrob. Agents Chemother. 2011, 55 (12), 5602.