Development of a synthetic route towards N4,N9-disubstituted 4,9-diaminoacridines: On the way to multi-stage antimalarials

[Display omitted] •Unprecedented 9-step route towards N4,N9-disubstituted 4,9-diaminoacridines, starting from 4-chlorosalicylic acid.•Insertion of the N9-substituent prior to the N4-substituent is preferable.•Nitro-aniline reduction step could only be achieved by using SnCl2/aq. HCl.•Target structur...

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Bibliographic Details
Published in:Tetrahedron letters 2019-04, Vol.60 (17), p.1166-1169
Main Authors: Fonte, Mélanie, Fagundes, Natália, Gomes, Ana, Ferraz, Ricardo, Prudêncio, Cristina, Araújo, Maria João, Gomes, Paula, Teixeira, Cátia
Format: Article
Language:English
Subjects:
Acridine
Antimalarial
Heteroaromatic
Heterocyclic chemistry
Mepacrine
Quinacrine
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Summary:[Display omitted] •Unprecedented 9-step route towards N4,N9-disubstituted 4,9-diaminoacridines, starting from 4-chlorosalicylic acid.•Insertion of the N9-substituent prior to the N4-substituent is preferable.•Nitro-aniline reduction step could only be achieved by using SnCl2/aq. HCl.•Target structures combine the pharmacophores of mepacrine, chloroquine and primaquine, three classical antimalarial drugs. A multi-step synthetic route towards N4,N9-disubstituted 4,9-diaminoacridines that, to the best of our knowledge, has no precedence in the literature, has been developed. The target structures are likely to reveal interesting biological activities in the near future, not only due to their mepacrine-like core, but also because they embed simultaneously the pharmacophores of chloroquine and primaquine, antimalarial drugs that act at different stages of malaria infection.
ISSN:0040-4039
1873-3581
DOI:10.1016/j.tetlet.2019.03.052