Synthesis of 3-azabicyclo[3.2.2]nonanes and their antiprotozoal activities

Werner Seebacher; Volker Wolkinger; Johanna Faist; Marcel Kaiser; Reto Brun; Robert Saf; Franz Bucar; Barbara Gröblacher; Adelheid Brantner; Virginia Merino; Yogeshvar Kalia; Leonardo Scapozza; Remo Perozzo; Robert Weis

doi:10.1016/j.bmcl.2015.02.044

Synthesis of 3-azabicyclo[3.2.2]nonanes and their antiprotozoal activities

Bioorg Med Chem Lett. 2015 Apr 1;25(7):1390-3. doi: 10.1016/j.bmcl.2015.02.044. Epub 2015 Feb 28.

Authors

Affiliations

¹ Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, Karl-Franzens-University, Schubertstrasse 1, Graz A-8010, Austria. Electronic address: we.seebacher@uni-graz.at.
² Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, Karl-Franzens-University, Schubertstrasse 1, Graz A-8010, Austria.
³ Swiss Tropical and Public Health Institute, Socinstrasse 57, Basel CH-4002, Switzerland; University of Basel, Petersplatz 1, Basel CH-4003, Switzerland.
⁴ Institute for Chemistry and Technology of Materials (ICTM), Graz University of Technology, Stremayrgasse 9, Graz A-8010, Austria.
⁵ Institute of Pharmaceutical Sciences, Pharmacognosie, Karl-Franzens-University, Universitätsplatz 4, Graz A-8010, Austria.
⁶ Departamento de Farmacia y Tecnología Farmacéutica, University of Valencia, Valencia E-46000, Spain.
⁷ School of Pharmaceutical Sciences, Pharmaceutical Biochemistry, University of Geneva, Quai Ernest-Ansermet 30, Geneva CH-1211, Switzerland.

PMID: 25746816
DOI: 10.1016/j.bmcl.2015.02.044

Abstract

Several bicyclic compounds, 3-azabicyclo[3.2.2]nonanes, have been prepared. The new compounds were tested for their activities against one strain of the causative organism of Malaria tropica, Plasmodium falciparum K1, which is resistant against chloroquine and pyrimethamine. In addition, their cytotoxicity and their activity against the pathogen of the East African form of sleeping sickness, Trypanosoma brucei rhodesiense, were investigated. Structure-activity relationships are discussed considering data of readily prepared compounds. For the first time, a distinct in vivo activity was observed against Plasmodium berghei in a mouse model. The active compound was further investigated.

Keywords: 3-Azabicyclo[3.2.2]nonanes; Antiplasmodial activity; Antitrypanosomal activity.

MeSH terms

Administration, Oral
Animals
Antiprotozoal Agents / administration & dosage
Antiprotozoal Agents / chemical synthesis
Antiprotozoal Agents / pharmacology*
Azabicyclo Compounds / chemical synthesis
Azabicyclo Compounds / chemistry
Azabicyclo Compounds / pharmacology*
Disease Models, Animal
Dose-Response Relationship, Drug
Injections, Intravenous
Male
Mice
Molecular Structure
Parasitic Sensitivity Tests
Plasmodium berghei / drug effects*
Plasmodium falciparum / drug effects*
Rats
Structure-Activity Relationship
Tissue Distribution
Trypanosoma brucei rhodesiense / cytology
Trypanosoma brucei rhodesiense / drug effects*
Trypanosomiasis, African / drug therapy*

Substances

Antiprotozoal Agents
Azabicyclo Compounds