Johanna Faist

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.

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.

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.

Antiprotozoal activity of bicyclic diamines with a N-methylpiperazinyl group at the bridgehead atom

ω-Aminoacyl and -alkyl derivatives of 4-(4-methylpiperazin-1-yl)bicyclo[2.2.2]octan-2-amines and of 5-(4-methylpiperazin-1-yl)-2-azabicyclo[3.2.2]nonanes were prepared and their activities were examined in vitro against the multiresistant K1 strain of Plasmodium falciparum and against Trypanosoma brucei rhodesiense (STIB 900). Some of the newly synthesized compounds showed very promising antiprotozoal activity and selectivity. A few of the alkylamino-2-azabicyclo[3.2.2]nonanes exhibited high antiplasmodial activity, whereas a single bicyclo[2.2.2]octane derivative was the most potent antitrypanosomal compound. The results of the newly synthesized compounds were compared with the activities of already synthesized compounds and of drugs in use. Structure-activity relationships were discussed.

Dialkylaminoalkyl derivatives of bicyclic compounds with antiplasmodial activity.

Dialkylaminoalkyl derivatives of 2-azabicyclo[3.2.2]nonanes and of bicyclo[2.2.2]octanes were prepared and their activities determined in vitro against the multiresistant K1 strain of Plasmodium falciparum. Several of the new compounds exhibited very promising antiplasmodial activity and selectivity. The results were compared to those of formerly synthesized analogues and of drugs in use. Structure-activity relationships were detected. Some of the more potent compounds were tested in vivo against Plasmodium berghei showing weak to moderate activity. A single compound was able to increase the mean survival days of infected mice.

Antiplasmodial and antitrypanosomal activity of bicyclic amides and esters of dialkylamino acids

Several bicyclic amides and esters of dialkylamino acids were prepared. Their activities against a multiresistant strain of Plasmodium falciparum and against Trypanosoma brucei rhodesiense (STIB 900) were examined. Structure-activity relationships were discussed. Particularly the ester compounds showed good antiplasmodial and antitrypanosomal activity and a single compound was tested in vivo against Plasmodium berghei.

Synthesis of new 4-phenylpyrimidine-2(1H)-thiones and their potency to inhibit COX-1 and COX-2

Several new 4-phenylpyrimidine-2(1H)-thiones have been prepared and investigated for their potencies to inhibit COX-1 and COX-2 enzymes, and COX-2 expression in THP-1 cells. Structure-activity-relationships and physicochemical parameters are discussed. Pharmacophore screening and docking studies were carried out for the most active compound.

Synthesis of antiprotozoal diamines by regioselective insertion of nitrogen into a bicyclic ring system

The regioselective insertion of nitrogen in a bicyclic octanone skeleton is reported. The structure was established by a single crystal structure analysis. The antiprotozoal activities of lactames and their reduction products were determined and discussed.Graphical Abstract

Alkyl and dialkylaminoethyl derivatives of 5-amino-2-azabicyclo[3.2.2]nonanes and their antiplasmodial and antitrypanosomal activities.

N-Alkyl and N-(2-dialkylaminoethyl) derivatives of 5-amino-2-azabicyclo-nonanes were prepared and tested in vitro for their activities against the multidrug-resistant K1 strain of Plasmodium falciparum and Trypanosoma brucei rhodesiense (STIB 900). Most of the new compounds showed lower antitrypanosomal activity than their parent compounds. With respect to their activity against P. falciparum the N-alkyl derivatives exhibited worse selectivity due to decreased antiplasmodial activity or higher cytotoxicity. In comparison all of the new N-(2-dialkylaminoethyl) analogues possessed a much better selectivity and a single of these compounds showed even better antiplasmodial activity and selectivity than chloroquine.

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

Some antimalarial agents in use typically bear basic side chains as ligands. Such ligands were attached to the amino substituent of a bridgehead atom of already antiprotozoal active 3-azabicyclo[3.2.2]nonanes. Structure verification was done by NMR measurements. The new compounds were tested for their antiplasmodial and antitrypanosomal activities against Plasmodium falciparumK1 (multiresistant) and Trypanosoma brucei rhodesiense as well as for their cytotoxicity against L6 cells. Their activities are compared to those of already prepared compounds and structure–activity relationships are discussed.