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Synthesis and antiplasmodial evaluation of novel mefloquine-based fumardiamides

The paper is focused on synthesis and screening of the antiplasmodial activity of novel fumardiamides 5–10 with the mefloquine pharmacophore and a Michael acceptor motif. Multi-step reactions leading to the title compounds included two amide bond formations. The first amide bond was achieved by the reaction of (E)-ethyl 4-chloro-4-oxobut-2- enoate (1) and N1-(2, 8- bis(trifluoromethyl)quinolin-4-yl)butane-1, 4- diamine (2). Basic hydrolysis of the obtained ester 3 afforded acid 4, which then reacted with the selected halogenanilines in the presence of HATU/DIEA and formed products 5–10. The title compounds showed significant, dose dependent activity in vitro against hepatic stages of Plasmodium berghei. IC50 values of the most active compounds 5, 7 and 9 bearing 3-fluoro, 3-chloro and 3-trifluoromethyl substituents were 3.04–4.16 µmol L–1, respectively. On the other hand, the compounds exerted only weak activity against the erythrocytic stages of two P. falciparum strains (Pf3D7 and PfDd2) in vitro, with the exception of compound 5 (IC50 = 2.9 µmol L–1).

Mefloquine ; 2, 8-bis(Trifluoromethyl)quinoline ; Fumardiamide, Halogenaniline, Antiplasmodial activity

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