title: Synthesis, biological characterisation and structure activity relationships of aromatic bisamidines active against Plasmodium falciparum.
abstract: 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.
authors.affiliation: Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120, Halle, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Sauer
authors.affiliation: Tropical Parasitology Lab, Eskitis Institute for Drug Discovery, Don Young Road, Griffith University, Nathan, Queensland, 4111, Australia.
authors.forename: T S
authors.initials: TS
authors.lastname: Skinner-Adams
authors.affiliation: U1019-CNRS UMR 8204, Univ. Lille Nord de France, Institut Pasteur de Lille, 1, Rue du professeur Calmette, 59019, Lille, France.
authors.forename: A
authors.initials: A
authors.lastname: Bouchut
authors.affiliation: Tropical Parasitology Lab, Eskitis Institute for Drug Discovery, Don Young Road, Griffith University, Nathan, Queensland, 4111, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Chua
authors.affiliation: U1019-CNRS UMR 8204, Univ. Lille Nord de France, Institut Pasteur de Lille, 1, Rue du professeur Calmette, 59019, Lille, France.
authors.forename: C
authors.initials: C
authors.lastname: Pierrot
authors.affiliation: Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120, Halle, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Erdmann
authors.affiliation: Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120, Halle, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Robaa
authors.affiliation: Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120, Halle, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: U1019-CNRS UMR 8204, Univ. Lille Nord de France, Institut Pasteur de Lille, 1, Rue du professeur Calmette, 59019, Lille, France.
authors.forename: J
authors.initials: J
authors.lastname: Khalife
authors.affiliation: Tropical Parasitology Lab, Eskitis Institute for Drug Discovery, Don Young Road, Griffith University, Nathan, Queensland, 4111, Australia.
authors.forename: K T
authors.initials: KT
authors.lastname: Andrews
authors.affiliation: Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120, Halle, Germany. Electronic address: wolfgang.sippl@pharmazie.uni-halle.de.
authors.forename: W
authors.initials: W
authors.lastname: Sippl
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D018938:Caco-2 Cells; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D057809:HEK293 Cells; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D005663:Furans; C469777:bisamidine
keywords: Bisamidine; Cytotoxicity; Furamidine; Plasmodium falciparum