Synthesis, biological characterisation and structure activity relationships of aromatic bisamidines active against Plasmodium falciparum

Malaria is one of the most significant tropical diseases and remains a major challenge due to the lack of a broadly effective vaccine and parasite resistance to current drugs. This means there is a need for new drug candidates with novel modes of action. Aromatic bisamidines, such as furamidine (DB7...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2017-02, Vol.127, p.22-40
Main Authors: Sauer, B., Skinner-Adams, T.S., Bouchut, A., Chua, M.J., Pierrot, C., Erdmann, F., Robaa, D., Schmidt, M., Khalife, J., Andrews, K.T., Sippl, W.
Format: Article
Language:English
Subjects:
Antimalarials - chemical synthesis
Antimalarials - chemistry
Antimalarials - pharmacology
Antimalarials - toxicity
Bisamidine
Caco-2 Cells
Chemistry Techniques, Synthetic
Cytotoxicity
Drug Design
Furamidine
Furans - chemical synthesis
Furans - chemistry
Furans - pharmacology
Furans - toxicity
HEK293 Cells
Humans
Plasmodium falciparum
Plasmodium falciparum - drug effects
Structure-Activity Relationship
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Summary:Malaria is one of the most significant tropical diseases and remains a major challenge due to the lack of a broadly effective vaccine and parasite resistance to current drugs. This means there is a need for new drug candidates with novel modes of action. Aromatic bisamidines, such as furamidine (DB75), were initially developed as anti-Trypanosoma agents however as clinical trials with furamidine highlighted potential side effects they were not pursued further in that setting. Despite apparent cytotoxicity liabilities the potency of furamidine against Plasmodium falciparum makes it a promising scaffold for the development of new anti-Plasmodium agents with improved selectivity. In this study a bisamidine compound series based on furamidine was synthesized by introducing modifications at the furan core structure and terminal amidine groups. The activity of the derived compounds was tested in vitro against drug sensitive and resistant P. falciparum lines and a human cell line (HEK293 cells) to generate anti-Plasmodium structure-activity relationships and to provide preliminary selectivity data. [Display omitted] •Novel symmetrical bisamidines based on furamidine were synthesized.•Their activity was tested in vitro against resistant P. falciparum strains.•Selectivity was determined using human HEK293 cell line.•Anti-Plasmodium structure-activity relationships and selectivity data were derived.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2016.12.041