Abstract
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.
Highlights
Over a half of the world’s population is at risk of an infection with malaria, especially children and pregnant women in developing countries like Africa
The lead structure 1 was prepared in a multi-step synthesis starting from 3(trifluoromethyl)anthranilic acid
This paper deals with the synthesis, antiplasmodial activities and first insights into structure-activity relationships of a series of new 2-phenoxybenzamides
Summary
Over a half of the world’s population is at risk of an infection with malaria, especially children and pregnant women in developing countries like Africa. In 2019 more than 229 million cases and over 400,000 deaths were reported [1]. Malaria is caused by singlecelled, eukaryotic protozoans of the species Plasmodium. Five of them are human pathogenic with Plasmodium falciparum causing the most deadly and dangerous Malaria tropica [2]. The current gold standard for malaria treatment are artemisinin-based combination therapies (ACTs). They are combinations of short-acting artemisinins with drugs with longer half-life and different mode of action. Progressive resistance development to ACTs in the Southeast
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