Acta Pharmaceutica, Vol. 69 No. 2, 2019.
Izvorni znanstveni članak
https://doi.org/10.2478/acph-2019-0019
Synthesis and antiplasmodial evaluation of novel mefloquine-based fumardiamides
MAJA BEUS
; University of Zagreb, Faculty of Pharmacy and Biochemistry, Department of Medicinal Chemistry, 10 000 Zagreb, Croatia
DIANA FONTHINA
; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
JANA HELD
; University of Tübingen, Institute of Tropical Medicine, 72 074 Tübingen, Germany
ZRINKA RAJIĆ
; University of Zagreb, Faculty of Pharmacy and Biochemistry, Department of Medicinal Chemistry, 10 000 Zagreb, Croatia
MIGUEL PRUDÊNCIO
; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
BRANKA ZORC
orcid.org/0000-0003-4355-8816
; University of Zagreb, Faculty of Pharmacy and Biochemistry, Department of Medicinal Chemistry, 10 000 Zagreb, Croatia
Sažetak
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).
Ključne riječi
mefloquine; 2,8-bis(trifluoromethyl)quinoline; fumardiamide; halogenaniline; antiplasmodial activity
Hrčak ID:
217028
URI
Datum izdavanja:
30.6.2019.
Posjeta: 1.380 *