Design, synthesis and antitrypanosomatid activities of 3,5-diaryl-isoxazole analogues based on neolignans veraguensin, grandisin and machilin G.
Chem Biol Drug Des
; 93(3): 313-324, 2019 03.
Article
em En
| MEDLINE
| ID: mdl-30354012
Using bioisosterism as a medicinal chemistry tool, 16 3,5-diaryl-isoxazole analogues of the tetrahydrofuran neolignans veraguensin, grandisin and machilin G were synthesized via 1,3-dipolar cycloaddition reactions, with yields from 43% to 90%. Antitrypanosomatid activities were evaluated against Trypanosoma cruzi, Leishmania (L.) amazonensis and Leishmania (V.) braziliensis. All compounds were selective for the Leishmania genus and inactive against T. cruzi. Isoxazole analogues showed a standard activity on both promastigotes of L. amazonensis and L. braziliensis. The most active compounds were 15, 16 and 19 with IC50 values of 2.0, 3.3 and 9.5 µM against L. amazonensis and IC50 values of 1.2, 2.1 and 6.4 µM on L. braziliensis, respectively. All compounds were noncytotoxic, showing lower cytotoxicity (>250 µM) than pentamidine (78.9 µM). Regarding the structure-activity relationship (SAR), the methylenedioxy group was essential to antileishmanial activity against promastigotes. Replacement of the tetrahydrofuran nucleus by an isoxazole core improved the antileishmanial activity.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Desenho de Fármacos
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Lignanas
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Furanos
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Isoxazóis
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Antiprotozoários
Limite:
Animals
Idioma:
En
Revista:
Chem Biol Drug Des
Assunto da revista:
BIOQUIMICA
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FARMACIA
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FARMACOLOGIA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Brasil
País de publicação:
Reino Unido