Research paper Synthesis, biological characterisation and structure activity relationships of aromatic bisamidines active against Plasmodium falciparum B. Sauer a , T.S. Skinner-Adams b , A. Bouchut c , M.J. Chua b , C. Pierrot c , F. Erdmann a , D. Robaa a , M. Schmidt a , J. Khalife c , K.T. Andrews b , W. Sippl a, * a Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120, Halle, Germany b Tropical Parasitology Lab, Eskitis Institute for Drug Discovery, Don Young Road, Griffith University, Nathan, Queensland, 4111, Australia c U1019-CNRS UMR 8204, Univ. Lille Nord de France, Institut Pasteur de Lille,1, Rue du professeur Calmette, 59019, Lille, France article info Article history: Received 21 October 2016 Received in revised form 19 December 2016 Accepted 20 December 2016 Available online 23 December 2016 Keywords: Plasmodium falciparum Bisamidine Furamidine Cytotoxicity 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 lia- bilities 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. © 2016 Elsevier Masson SAS. All rights reserved. 1. Introduction Malaria is an infectious hematologic disease that is caused by different Plasmodium species. Infection with Plasmodium falciparum can lead to severe symptoms, with >200 million clinical cases and ~450,000 malaria-related deaths occurring annually [1]. Clinical manifestations of malaria are induced by the asexual stages of the parasite that develop inside red blood cells [2] and it is this lifecycle stage that is the primary target of most treatment drugs. Over the past two decades, there has been significant reduction in the number of malaria cases and, since 2000, malaria-related deaths have halved [1,3]. Despite these gains, the emergence of drug resistant P. falciparum parasites and reduced clinical efficacy of current drugs, including the gold standard artemisinin combination therapies (ACTs) is a major obstacle and is fueling the discovery of new alternatives [4]. To address the need for new treatment options for malaria, new chemical entities with different modes of action to currently used antimalarial agents are needed. Among bis-tertiary amines, bis- quaternary ammonium salts and bis-2-aminopyridinium salts also aliphatic guanidines and aliphatic amidines were subjects of investigation to antimalarial activity [5]. Bisamidines are well known for their wide range of biological activities including anti- microbial, anti-inflammatory and anticancer effects [6]. The dibenzenecarboximidamide derivative, pentamidine, is used clini- cally for the treatment of leishmaniasis, trypanosomiasis and pneumocystis pneumonia [7]. Pentamidine is thought to act through blocking replication of parasite kinetoplast DNA in Leish- mania parasites [8]. Due to a lack of alternatives, pentamidine is still used despite its potential life-threatening side effects. Investigation of pentamidine alternatives resulted in the discovery of the furan derivative furamidine (also known as DB75; Fig. 1). Furamidine is a fluorescent structural analogue of pentamidine with activity against trypanosoma sp, Pneumocystis carinii, Cryptosporidium par- vum [9e12], and in vitro cultured asexual intraerythrocytic stage P. falciparum K1 parasites (IC 50 15.5 nM) [13], but with low oral * Corresponding author. Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany. E-mail address: wolfgang.sippl@pharmazie.uni-halle.de (W. Sippl). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech http://dx.doi.org/10.1016/j.ejmech.2016.12.041 0223-5234/© 2016 Elsevier Masson SAS. All rights reserved. European Journal of Medicinal Chemistry 127 (2017) 22e40