Acta Pharm. 69 (2019) 233-248

full paper

Original research paper

Synthesis and antiplasmodial evaluation of novel mefloquine-based fumardiamides

MAJA BEUS, DIANA FONTINHA, JANA HELD, ZRINKA RAJIĆ, MIGUEL PRUDÊNCIO and BRANKA ZORC

bzorc@pharma.hr

¹ University of Zagreb, Faculty of Pharmacy and Biochemistry, Department of Medicinal Chemistry
10 000 Zagreb, Croatia

² Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa
1649-028 Lisboa, Portugal

³ University of Tübingen, Institute of Tropical Medicine, 72 074 Tübingen, Germany

Accepted February 14, 2019

Published online February 28, 2019

The paper is focused on the 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). The obtained ester 3 was hydrolysed and gave acid 4, which then reacted with the selected halogenanilines in the presence of HATU/DIEA and formed products 5–10. Title compounds showed marked, 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).

Keywords: mefloquine, 2,8-bis(trifluoromethyl)quinoline, fumardiamide, halogenaniline, antiplasmodial activity