Antileishmanial Activity and Structure-Activity Relationship of Triazolic Compounds Derived from the Neolignans Grandisin, Veraguensin, and Machilin G

Abstract

Sixteen 1,4-diaryl-1,2,3-triazole compounds 4-19 derived from the tetrahydrofuran neolignans veraguensin 1, grandisin 2, and machilin G 3 were tested against Leishmania (Leishmania) amazonensis intracellular amastigotes. Triazole compounds 4-19 were synthetized via Click Chemistry strategy by 1,3-dipolar cycloaddition between terminal acetylenes and aryl azides containing methoxy and methylenedioxy groups as substituents. Our results suggest that most derivatives were active against intracellular amastigotes, with IC 50 values ranging from 4.4 to 32.7 µM. The index of molecular hydrophobicity (ClogP) ranged from 2.8 to 3.4, reflecting a lipophilicity/hydrosolubility rate suitable for transport across membranes, which may have resulted in the potent antileishmanial activity observed. Regarding structure-activity relationship (SAR), compounds 14 and 19, containing a trimethoxy group, were the most active (IC 50 values of 5.6 and 4.4 µM, respectively), with low cytotoxicity on mammalian cells (SI = 14.1 and 10.6). These compounds induced nitric oxide production by the host macrophage cells, which could be suggested as the mechanism involved in the intracellular killing of parasites. These results would be useful for the planning of new derivatives with higher antileishmanial activities.

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

“…Untreated cells were used as a negative control. After treatment, coverslips were removed, fixed, stained with Giemsa (Sigma‐Aldrich), and diluted in 1:10 proportion in distilled water (Costa et al, ). The total number of amastigotes was determined by counting 200 cells per coverslip, in six replicates.…”

“…The antitrypanosomatid activities of these compounds were tested in vitro. Isoxazole analogues 16′–19′ proved to be as active as 1,2,3‐triazole congeners 16–19 against promastigotes of Leishmania species (Cassamale et al, ; Costa et al, ; Trefzger et al, ). SAR analysis showed that the methylenedioxy group as a substituent was critical to the antileishmanial activity against promastigotes (Figure ).…”

“…Despite their significant antileishmanial activity against promastigote forms, in order to enhance the SAR, study of 1,2,3‐triazoles 16–19 is also necessary to evaluate the biological response against amastigote forms (Costa et al, ). The reference drug pentamidine used in this study was active on both promastigote and amastigote forms; therefore, compounds that show biological activity against amastigotes should be promising for in vivo studies.…”

“…In general, the in vitro assay is performed on promastigotes as a screening technique in compound libraries, due to the more rapid data analysis, which is a characteristic of the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide method (Cassamale et al, ; Trefzger et al, ). In contrast, the antileishmanial assay on amastigotes is laborious and the results are acquired slowly (Costa et al, ).…”

“…The main aim of this study was to evaluate the in vitro antileishmanial activity of isoxazole analogues 4′–19′ (Table ) on intracellular amastigote forms of Leishmania ( L. ) amazonensis. This study also compared the SAR between 1,2,3‐triazole (Costa et al, ) and isoxazole analogues with the same substitution pattern.…”