Advertisement

Archives of Pharmacal Research

, Volume 39, Issue 10, pp 1391–1403 | Cite as

The antiprotozoal potencies of newly prepared 3-azabicyclo[3.2.2]nonanes

  • Sarfraz Ahmad
  • Werner Seebacher
  • Johanna Faist
  • Marcel Kaiser
  • Reto Brun
  • Robert Saf
  • Robert Weis
Research Article

Abstract

3-Azabicyclo[3.2.2]nonanes are already reported as antiprotozoal agents. Structural variations were performed by attachment of several basic side chains, being part of drugs in use, to the ring nitrogen. The structures of the new compounds were established using one and two dimensional NMR measurements. All compounds were investigated for their antiplasmodial and antitrypanosomal activities against Plasmodium falciparum K 1 (multiresistant) and Trypanosoma brucei rhodesiense. Their cytotoxicity was assessed against L6 cells. The results are compared to the activities of formerly synthesized compounds. Structure–activity relationships are discussed.

Keywords

3-Azabicyclo[3.2.2]nonanes Basic side chains Antimalarial activity Antitrypanosomal activity Structure–activity relationships 

Supplementary material

12272_2016_826_MOESM1_ESM.doc (96 kb)
Supplementary material 1 (DOC 95 kb)

References

  1. Ahmad S, Seebacher W, Wolkinger V, Presser A, Faist J, Kaiser M, Brun R, Saf R, Weis R (2014) Synthesis and antiprotozoal activities of new 3-azabicyclo[3.2.2]nonanes. Arch Pharm Res 38:1455–1467CrossRefPubMedGoogle Scholar
  2. Baltz T, Baltz D, Giroud C, Crockett J (1985) Cultivation in a semi-defined medium of animal infective forms of Trypanosoma brucei, T. equiperdum, T. evansi, T. rhodesiense and T. gambiense. EMBO J 4:1273–1277PubMedPubMedCentralGoogle Scholar
  3. Bijker EM, Borrmann S, Kappe SH, Mordmüller B, Sack BK, Khan SM (2015) Novel approaches to whole sporozoite vaccination against malaria. Vaccine 33:7462–7468CrossRefPubMedGoogle Scholar
  4. Franke-Fayard B, Trueman H, Ramesar J, Mendoza J, Van der Keur M, Van der Linden R, Sinden RE, Waters AP, Janse CJ (2004) Plasmodium berghei reference line that constitutively expresses GFP at a high level throughout the complete life cycle. Mol Biochem Parasitol 137:23–33CrossRefPubMedGoogle Scholar
  5. Glaser R, Bernstein MA, Balan A (1991) 1H and 13C NMR studies on the conformation of E, Z-diastereomers of N-desmethyl-N, O-diacetyl-α-metazocine (sp2-hybridized nitrogen derivatives of a benzomorphan narcotic analgesic). Magn Reson Chem 29:766–773CrossRefGoogle Scholar
  6. Kato CD, Alibu VP, Nanteza A, Mugasa CM, Matovu E (2015) Interleukin (IL)-6 and IL-10 are up regulated in late stage Trypanosoma brucei rhodesiense sleeping sickness. PLoS Negl Trop Dis 9(6):e0003835. doi: 10.1371/journal.pntd.0003835 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Kennedy PGE (2006) Diagnostic and neuropathogenesis issues in human African trypanosomiasis. Int J Parasitol 36:505–512CrossRefPubMedGoogle Scholar
  8. Matile H, Pink JRL (1990) Plasmodium falciparum malaria parasite cultures and their use in immunology. In: Lefkovits L, Pernis B (eds) Immunological Methods. Academic Press, San Diego, pp 221–234CrossRefGoogle Scholar
  9. N-ul-A Mohsin, Seebacher W, Faist J, Belaj F, Saf R, Kaiser M, Brun R, Weis R (2014) Synthesis of antiprotozoal diamines by regioselective insertion of nitrogen into a bicyclic ring system. Monatsh Chem 145:1319–1327CrossRefGoogle Scholar
  10. Peters W (1987) Chemotherapy and drug resistance in Malaria, vol 1. Academic Press, LondonGoogle Scholar
  11. Räz B, Iten M, Grether-Bühler Y, Kaminsky R, Brun R (1997) The Alamar Blue assay to determine drug sensitivity of African trypanosomes (T. b. rhodesiense and T. b. gambiense) in vitro. Acta Trop 68:139–147CrossRefPubMedGoogle Scholar
  12. Seebacher W, Weis R (2011) Novel antimalarial 3-azabicyclo[3.2.2]nonane derivatives. Int Patent, WO 2011/035355 A1Google Scholar
  13. Seebacher W, Wolkinger V, Faist J, Kaiser M, Brun R, Saf R, Bucar F, Gröblacher B, Brantner A, Merino V, Kalia Y, Scapozza L, Perozzo R, Weis R (2015) Synthesis of 3-azabicyclo[3.2.2]nonanes and their antiprotozoal activities. Bioorg Med Chem Lett 25:1390–1393CrossRefPubMedGoogle Scholar
  14. Taleli L, de Kock C, Smith PJ, Pelly SC, Blackie MAL, van Otterlo WAL (2015) In vitro antiplasmodial activity of triazole-linked chloroquinoline derivatives synthesized from 7-chloro-N-(prop-2-yn-1-yl)quinolin-4-amine. Bioorg Med Chem 23:4163–4171CrossRefPubMedGoogle Scholar
  15. Weis R, Schweiger K, Seebacher W, Belaj F (1998) One-pot synthesis of 4-Aminobicyc-lo[2.2.2]octan-2-ones. Tetrahedron 54:14015–14022CrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2016

Authors and Affiliations

  1. 1.Center for Research in Molecular MedicineThe University of LahoreLahorePakistan
  2. 2.Institute of Pharmaceutical Sciences, Pharmaceutical ChemistryUniversity of GrazGrazAustria
  3. 3.Swiss Tropical and Public Health InstituteBaselSwitzerland
  4. 4.Institute for Chemistry and Technology of Materials (ICTM)Graz University of TechnologyGrazAustria
  5. 5.University of BaselBaselSwitzerland

Personalised recommendations