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 acceptor motif. Multi-step reactions leading to the title compounds included two amide bond formations. The first amide bond was achieved by...
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| Format: | Article |
| Language: | English |
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Sciendo
2019-06-01
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| Series: | Acta Pharmaceutica |
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| Online Access: | https://doi.org/10.2478/acph-2019-0019 |
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| author | Beus Maja Fontinha Diana Held Jana Rajić Zrinka Prudêncio Miguel Zorc Branka |
| author_facet | Beus Maja Fontinha Diana Held Jana Rajić Zrinka Prudêncio Miguel Zorc Branka |
| author_sort | Beus Maja |
| collection | DOAJ |
| description | 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). |
| format | Article |
| id | doaj-art-adc96e4f36284f34aa33207dd71c955c |
| institution | Kabale University |
| issn | 1846-9558 |
| language | English |
| publishDate | 2019-06-01 |
| publisher | Sciendo |
| record_format | Article |
| series | Acta Pharmaceutica |
| spelling | doaj-art-adc96e4f36284f34aa33207dd71c955c2025-02-02T00:31:54ZengSciendoActa Pharmaceutica1846-95582019-06-0169223324810.2478/acph-2019-0019acph-2019-0019Synthesis and antiplasmodial evaluation of novel mefloquine-based fumardiamidesBeus Maja0Fontinha Diana1Held Jana2Rajić Zrinka3Prudêncio Miguel4Zorc Branka5University of Zagreb Faculty of Pharmacy and BiochemistryDepartment of Medicinal Chemistry10 000Zagreb, CroatiaInstituto de Medicina Molecular Faculdade de Medicina, Universidade de Lisboa, 1649-028Lisboa, PortugalUniversity of Tübingen Institute of Tropical Medicine72 074Tübingen, GermanyUniversity of Zagreb Faculty of Pharmacy and BiochemistryDepartment of Medicinal Chemistry10 000Zagreb, CroatiaInstituto de Medicina Molecular Faculdade de Medicina, Universidade de Lisboa, 1649-028Lisboa, PortugalUniversity of Zagreb Faculty of Pharmacy and BiochemistryDepartment of Medicinal Chemistry10 000Zagreb, CroatiaThe 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).https://doi.org/10.2478/acph-2019-0019mefloquine2,8-bis(trifluoromethyl)quinolinefumardiamidehalogenanilineantiplasmodial activity |
| spellingShingle | Beus Maja Fontinha Diana Held Jana Rajić Zrinka Prudêncio Miguel Zorc Branka Synthesis and antiplasmodial evaluation of novel mefloquine-based fumardiamides Acta Pharmaceutica mefloquine 2,8-bis(trifluoromethyl)quinoline fumardiamide halogenaniline antiplasmodial activity |
| title | Synthesis and antiplasmodial evaluation of novel mefloquine-based fumardiamides |
| title_full | Synthesis and antiplasmodial evaluation of novel mefloquine-based fumardiamides |
| title_fullStr | Synthesis and antiplasmodial evaluation of novel mefloquine-based fumardiamides |
| title_full_unstemmed | Synthesis and antiplasmodial evaluation of novel mefloquine-based fumardiamides |
| title_short | Synthesis and antiplasmodial evaluation of novel mefloquine-based fumardiamides |
| title_sort | synthesis and antiplasmodial evaluation of novel mefloquine based fumardiamides |
| topic | mefloquine 2,8-bis(trifluoromethyl)quinoline fumardiamide halogenaniline antiplasmodial activity |
| url | https://doi.org/10.2478/acph-2019-0019 |
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