Werner Seebacher

One-pot synthesis of 4-aminobicyclo[2.2.2]octan-2-ones

Abstract Dialkylammonium rhodanides and benzylidene acetone give racemic (6RS,7RS)-4-dialkylamino-bicyclo[2.2.2]octan-2-ones in a one-pot reaction in good yields. The mechanism of the reaction includes a Diels-Alder step. The structures are established by NMR spectra and a single crystal structure analysis. The compounds consist of cations of racemates of optically active (6R,7R)- and (6S,7S)-4-dialkylamino-6,7-diphenylbicyclo[2.2.2]octan-2-ones and isothiocyanate anions.

Antimycobacterial and H1-antihistaminic activity of 2-substituted piperidine derivatives.

2-Substituted derivatives of the antihistaminic agents Bamipine, Diphenylpyraline and of their 1-phenyl analogues were tested for their antimycobacterial and H(1)-antagonistic activities. They are strong H1-receptor antagonists and also inhibit the growth of mycobacterials with a maximum MIC of 6.25 microg/mL against Mycobacterium tuberculosis H(37)Rv. H1-receptor antagonistic potency was slightly decreased by substitution in ring position 2 and distinctly diminished by N-aryl substitution. The antimycobacterial potency of Diphenylpyraline was in general increased by substitution in ring position 2, whereas only a few Bamipine derivatives showed markedly improved activity. A correlation between the two activities was not detected for those compounds.

One-pot syntheses of 2-pyrazoline derivatives

Abstract Hydrazinediium dithiocyanate and α,β-unsaturated ketones give in one-pot reactions 1-thiocarbamoyl-2-pyrazolines and 1-formyl-2-pyrazolines. The syntheses of pyridine-2-thiones, pyrimidine-2-thiones and bicyclo[2.2.2]octan-2-ones from ammonium thiocyanates and ketones by analogous procedures are reviewed. The mechanisms of the ring formations are discussed. Crystal structure analyses of a 1-thiocarbamoyl- and a 1-formyl-2-pyrazoline are given.

Synthesis of new triazepinethiones

Abstract We describe the first synthesis of 7-alkyl-5-aryl-1,2,4-triazepine-3-thiones using hydrazinediium dithiocyanate and α,β-unsaturated ketones as starting materials. Triazepine-3-thiones with this substitution pattern are not accessible by former reported methods. Those compounds may serve as black toning agents for laminated photographs or as starting materials for the synthesis of thiazolo[3,2- b ][1,2,4]triazepines, which are supposed to have immunomodulating activities.

Synthesis and hemolytic properties of lactosides of glycyrrhetic acid derivatives

Summary. The partial synthesis of lactosides of glycyrrhetic acid, its 11-deoxo and 18α-derivatives, and their methyl esters is described. The influence of the aglycon structure on the hemolytic properties of the title compounds is discussed and compared with those of oleanolic acid derivatives. Furthermore, we describe an optimized preparation of 18α-glycyrrhetic acid.

Synthesis of bicyclic amines and their activities against Trypanosoma brucei rhodesiense and Plasmodium falciparum K1

New alkenes, aziridines, and diamines were prepared from antiprotozoal 4-dialkylaminobicyclo[2.2.2]octan-2-imines to investigate the influence of several functional groups in position 2 of the ring skeleton on the antitrypanosomal and antiplasmodial activities. They were synthesized from 4-dialkylaminobicyclo[2.2.2]octan-2-imines and tested for their activities against Trypanosoma b. rhodesiense and Plasmodium falciparum K1 (resistant to chloroquine and pyrimethamine) using in vitro microplate assays. 4-Aminobicyclo[2.2.2]oct-2-enes and 3-azatricyclo[3.2.2.02,4]nonylamines exhibit similar antiprotozoal activities as 4-aminobicyclo[2.2.2] octanes. 4-Aminobicyclo[2.2.2]oct-2-ylamines and their N-benzyl derivatives showed decreased antiplasmodial but enhanced antitrypanosomal (IC50 = 0.22−0.41 μM) activities compared to their parent oximes and to formerly synthesized 4-amino-2-azabicyclo[3.2.2]nonanes. Some of the 4-aminobicyclo[2.2.2]oct-2-ylamines exhibit moderate in vivo activity in mice against Trypanosoma brucei brucei.

SYNTHESIS AND HAEMOLYTIC ACTIVITY OF RANDIANIN ISOMERS

Summary. Randianin, a haemolytic active saponin from Randia dumetorum, and some of its isomers with different carbohydrate side chains have been synthesized from oleanolic acid. The influence of the linkage within the disaccharide residue on the haemolytic activity of these glycosides has been investigated.Zusammenfassung. Randianin, ein hämolytisches Saponin aus Randia dumetorum, sowie einige dazu isomere Glycoside wurden ausgehend von Oleanolsäure synthetisiert. Der Einfluß der Verknüpfung in der Dissaccharidseitenkette auf die hämolytische Wirkung dieser Glycoside wurde untersucht.

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

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.

1,2-substituted 4-(1H)-quinolones : synthesis, antimalarial and antitrypanosomal activities in vitro

A diverse array of 4-(1H)-quinolone derivatives bearing substituents at positions 1 and 2 were synthesized and evaluated for antiprotozoal activities against Plasmodium falciparum and Trypanosoma brucei rhodesiense, and cytotoxicity against L-6 cells in vitro. Furthermore, selectivity indices were also determined for both parasites. All compounds tested showed antimalarial activity at low micromolar concentrations, with varied degrees of selectivity against L-6 cells. Compound 5a was found to be the most active against P. falciparum, with an IC50 value of 90 nM and good selectivity for the malarial parasite compared to the L-6 cells. Compound 10a, on the other hand, showed a strong antitrypanosomal effect with an IC50 value of 1.25 µM. In this study side chain diversity was explored by varying the side chain length and substitution pattern on the aliphatic group at position-2 and a structure-antiprotozoal activity study revealed that the aromatic ring introduced at C-2 contributed significantly to the antiprotozoal activities.

Antiplasmodial and antitrypanosomal activities of aminobicyclo[2.2.2]octyl ω-aminoalkanoates

Several 4-aminobicyclo[2.2.2]octyl esters of omega-dialkylamino acids were prepared. Their activities against the multidrug-resistant K(1) strain of Plasmodium falciparum and Trypanosoma brucei rhodesiense (STIB 900) were determined using microplate assays and compared to those of formerly prepared analogues. The biological activity was influenced by the relative configuration in ring position 2, by the chain length of the acid moiety and by the amino substitution. The most active antiplasmodial ester was as active as chloroquine. One of the new compounds exhibited the highest antitrypanosomal activity and selectivity of all bicyclo-octane derivatives prepared so far.