New 2-aminopyrimidine derivatives and their antitrypanosomal and antiplasmodial activities
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ORIGINAL PAPER
New 2‑aminopyrimidine derivatives and their antitrypanosomal and antiplasmodial activities Michael Hoffelner1 · Usama Hassan1 · Werner Seebacher1 · Johanna Dolensky1 · Patrick Hochegger1 · Marcel Kaiser2 · Pascal Mäser2 · Robert Saf3 · Robert Weis1 Received: 19 June 2020 / Accepted: 10 August 2020 © The Author(s) 2020
Abstract 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
Keywords Antiplasmodial activity · Antitrypanosomal activity · Heterocycles · Drug research · Structure–activity relationships
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00706-020-02674-7) contains supplementary material, which is available to authorized users. * Werner Seebacher we.seebacher@uni‑graz.at 1
Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria
2
Swiss Tropical and Public Health Institute and University of Basel, Basel, Switzerland
3
Institute for Chemistry and Technology of Materials (ICTM), Graz University of Technology, Graz, Austria
In the past two decades, over two billion of the world’s poorest people have been affected by neglected tropical diseases (NTDs). One of the 11 major NTDs studied is human African trypanosomiasis (HAT) [1]. HAT or sleeping sickness is caused by protozoa of the genus Trypanosoma like Trypanosoma brucei gambiense (Tbg) and Trypanosoma brucei rhodesiense (Tbr). The vector is the tsetse fly. Only one drug, melarsoprol, is available for the late-stage Tbr infection treatment [2]. This toxic arsenic compound causes severe side effects including a deadly encephalopathy in more than 5% of the patients [3]. Therefore it is an urgent
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chloroform yielding 4a–4d. The next step was an oxidation to the methylsulfonyl compounds 5a–5d with m-chloro perbenzoic acid in dichloromethane. The final formation of the target compounds 6–10 took place in dioxane or tetrahydrofuran in the presence of the various amines under microwave irradiation at 120 °C or under reflux. Structural modifications were restricted to the amino substituent including amino, a (p
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