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Effect of isoxazole derivatives of tetrahydrofuran neolignans on intracellular amastigotes of Leishmania ( Leishmania ) amazonensis : A structure–activity relationship comparative study with triazole‐neolignan‐based compounds
Author(s) -
Neves Amarith R.,
Trefzger Ozildéia S.,
Barbosa Natália V.,
Honorato Antonio M.,
Carvalho Diego B.,
Moslaves Iluska S.,
Kadri Mônica C. T.,
Yoshida Nidia C.,
Kato Massuo J.,
Arruda Carla C. P.,
Baroni Adriano C. M.
Publication year - 2019
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13609
Subject(s) - isoxazole , amastigote , chemistry , leishmania , stereochemistry , intracellular , triazole , biochemistry , parasite hosting , organic chemistry , world wide web , computer science
Isoxazole analogues derived from the neolignans veraguensin, grandisin, and machilin G were previously synthesized with different substitution patterns through the bioisosterism strategy. These compounds were tested on intracellular amastigotes of Leishmania (Leishmania) amazonensis ; the derivatives proved to be active against intracellular amastigotes, with IC 50 values ranging from 0.4 to 25 μM. The most active analogues were 4′ , 14′ , 15′, and 18′ , with IC 50 values of 0.9, 0.4, 0.7, and 1.4 μM, respectively, showing high selectivity indexes (SI = 277.0; 625.0; 178.5 and 357.1). Overall, the isoxazole analogues did not induce nitric oxide (NO) production by infected cells; there was no evidence that NO influences the antileishmanial mechanism of action, except for compound 4′ . Trimethoxy groups as substituents seemed to be critical for antileishmanial activity. The SAR study demonstrated that the isoxazole compounds were more active than 1,2,3‐triazole compounds with the same substitution pattterns, demonstrating the importance of the bioisosterism strategy in drug design.