N-(Aminoalkyl)azabicyclo[3.2.2]nonanes possess antiplasmodial and antitrypanosomal activity. A series with terminal tetrazole or sulfonamido partial structure was prepared. The structures of all new compounds were confirmed by NMR and IR spectroscopy and by mass spectral data. A single crystal structure analysis enabled the distinction between isomers. The antiprotozoal activities were examined in vitro against strains of Plasmodium falciparum and Trypanosoma brucei rhodesiense (STIB 900). The most active sulfonamide and tetrazole derivates showed activities in the submicromolar range.

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An N-acylated furazan-3-amine of a Medicines for Malaria Venture (MMV) project has shown activity against different strains of Plasmodium falciparum. Seventeen new derivatives were prepared and tested in vitro for their activities against blood stages of two strains of Plasmodium falciparum. Several structure–activity relationships were revealed. The activity strongly depended on the nature of the acyl moiety. Only benzamides showed promising activity. The substitution pattern of their phenyl ring affected the activity and the cytotoxicity of compounds. In addition, physicochemical parameters were calculated (log P, log D, ligand efficiency) or determined experimentally (permeability) via a PAMPA. The N-(4-(3,4-diethoxyphenyl)-1,2,5-oxadiazol-3-yl)-3-(trifluoromethyl)benzamide possessed good physicochemical properties and showed high antiplasmodial activity against a chloroquine-sensitive strain (IC50(NF54) = 0.019 µM) and even higher antiplasmodial activity against a multiresistant strain (IC50(K1) = 0.007 µM). Compared to the MMV compound, the permeability and the activity against the multiresistant strain were improved.

2,4-Diaminopyrimidines and (dialkylamino)azabicyclo-nonanes possess activity against protozoan parasites. A series of fused hybrids were synthesized and tested in vitro against pathogens of malaria tropica and sleeping sickness. The activities and selectivities of compounds strongly depended on the substitution pattern of both ring systems as well as on the position of the nitrogen atom in the bicycles. The most promising hybrids of 3-azabicyclo-nonane with 2-aminopyrimidine showed activity against P. falciparum NF54 in submicromolar concentration and high selectivity. A hybrid with pyrrolidino substitution of the 2-azabicyclo-nonane as well as of the pyrimidine moiety exhibited promising activity against the multiresistant K1 strain of P. falciparum. A couple of hybrids of 2-azabicyclo-nonanes with 2-(dialkylamino)pyrimidines possessed high activity against Trypanosoma brucei rhodesiense STIB900 and good selectivity.

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The 2-phenoxybenzamide 1 from the Medicines for Malaria Venture Malaria Box Project has shown promising multi-stage activity against different strains of P. falciparum. It was successfully synthesized via a retrosynthetic approach. Subsequently, twenty-one new derivatives were prepared and tested for their in vitro activity against blood stages of the NF54 strain of P. falciparum. Several insights into structure-activity relationships were revealed. The antiplasmodial activity and cytotoxicity of compounds strongly depended on the substitution pattern of the anilino partial structure as well as on the size of substituents. The diaryl ether partial structure had further impacts on the activity. Additionally, several physicochemical and pharmacokinetic parameters were calculated (log P, log D7.4 and ligand efficiency) or determined experimentally (passive permeability and CYP3A4 inhibition). The tert-butyl-4-{4-[2-(4-fluorophenoxy)-3-(trifluoromethyl)benzamido]phenyl}piperazine-1-carboxylate possesses high antiplasmodial activity against P. falciparum NF54 (PfNF54 IC50 = 0.2690 µM) and very low cytotoxicity (L-6 cells IC50 = 124.0 µM) resulting in an excellent selectivity index of 460. Compared to the lead structure 1 the antiplasmodial activity was improved as well as the physicochemical and some pharmacokinetic parameters.

A new series of compounds was prepared from 6-methoxyquinolin-8-amine or its N-(2-aminoethyl) analogue via Ugi-azide reaction. Their linkers between the quinoline and the tert-butyltetrazole moieties differ in chain length, basicity and substitution. Compounds were tested for their antiplasmodial activity against Plasmodium falciparum NF54 as well as their cytotoxicity against L-6-cells. The activity and the cytotoxicity were strongly influenced by the linker and its substitution. The most active compounds showed good activity and promising selectivity.

Novel 2-aminopyrimidine derivatives were prepared from acyclic starting materials, benzylidene acetones and ammonium thiocyanates, via 5 steps, including ring closure, aromatization, S-methylation, oxidation to methylsulfonyl compounds, and formation of guanidines with suitable amines. The prepared compounds differ from each other by the substitutions of their amino group and of their phenyl ring. The 2-aminopyrimidines were tested by use of microplate assays for their in vitro activities against a causative organism of sleeping sickness, Trypanosoma brucei rhodesiense, as well as against a causative organism of malaria, Plasmodium falciparum NF54. Their cytotoxic properties were determined with L-6 cells (rat skeletal myoblasts). Some of the compounds exhibited quite good antitrypanosomal activity, and others showed excellent antiplasmodial activity. The influence of the structural modifications on these activities is discussed. Graphic abstract