<abstract xmlns="http://www.w3.org/1999/xhtml">The paper is focused on the synthesis and screening of the antiplasmodial activity of novel fumardiamides <bold>5–10</bold> 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 (<italic>E</italic>)-ethyl 4-chloro-4-oxobut-2-enoate (<bold>1</bold>) and <italic>N</italic>1-(2,8-bis(trifluoromethyl)quinolin-4-yl) butane-1,4-diamine (<bold>2</bold>). The obtained ester <bold>3</bold> was hydrolyzed and gave acid <bold>4</bold>, which then reacted with the selected halogenanilines in the presence of HATU/DIEA and formed products <bold>5–10</bold>. Title compounds showed marked, dose dependent activity <italic>in vitro</italic> against hepatic stages of <italic>Plasmodium berghei. IC</italic>50 values of the most active compounds <bold>5</bold>, <bold>7</bold> and <bold>9</bold> 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 <italic>P. falciparum</italic> strains (<italic>Pf</italic>3D7 and <italic>Pf</italic>Dd2) <italic>in vitro</italic>, with the exception of compound <bold>5</bold> (<italic>IC</italic>50 = 2.9 µmol L−1).</abstract>

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 hydrolyzed 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).

Synthesis and antiplasmodial evaluation of novel mefloquine-based fumardiamides

University of Zagreb Faculty of Pharmacy and Biochemistry

University of Tübingen Institute of Tropical Medicine

Acta Pharmaceutica

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

{"article-title":"Synthesis and antiplasmodial evaluation of novel mefloquine-based fumardiamides"}

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...

Synthesis and antiplasmodial evaluation of novel mefloquine-based fumardiamides

Pubblicato online: 28 mar 2019

Pagine: 233 - 248

Accettato: 14 feb 2019

DOI: https://doi.org/10.2478/acph-2019-0019

Parole chiave
mefloquine, 2,8-bis(trifluoromethyl)quinoline, fumardiamide, halogenaniline, antiplasmodial activity

© 2019 Maja Beus et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Synthesis and antiplasmodial evaluation of novel mefloquine-based fumardiamides

Pubblicato online: 28 mar 2019

Pagine: 233 - 248

Accettato: 14 feb 2019

DOI: https://doi.org/10.2478/acph-2019-0019

Parole chiavemefloquine, 2,8-bis(trifluoromethyl)quinoline, fumardiamide, halogenaniline, antiplasmodial activity

© 2019 Maja Beus et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Parole chiave
mefloquine, 2,8-bis(trifluoromethyl)quinoline, fumardiamide, halogenaniline, antiplasmodial activity