Synthesis and Antitrypanosomastid Activity of 1,4-Diaryl-1,2,3-triazole Analogues of Neolignans Veraguensin, Grandisin and Machilin G

Abstract

Sixteen 1,4-diaryl-1,2,3-triazole compounds derived from the natural products veraguensin, grandisin and machilin G were synthesized, with yields of 78-92%. Biological activity tests against Leishmania amazonensis promastigotes showed that three of these compounds were the most active, with maximum inhibitory concentration (IC 50 ) values of 1.1, 3.71 and 7.23 µM. One compound was highly active against Leishmania infantum, with an IC 50 value of 5.2 µM, and one derivative showed an IC 50 value of 28.6 µM against Trypanosoma cruzi trypomastigotes. Regarding structureactivity relationship (SAR), hybrid 1,2,3-triazolic compounds containing a methylenedioxy group, showed the best antileishmanial and antitrypanosomal activities.

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

“…These compounds have been considered important scaffolds in molecular modification studies due to their antileishmanial and antichagasic activities [13][14][15][16]. Cassamale et al [12] demonstrated the antileishmanial activity of these triazole derivatives on promastigote forms; now the present work shows their activity on L. (L.) amazonensis intracellular amastigotes, searching for structure-activity relationship information to support the development of new drug candidates for CL.…”

“…19 has significantly reduced the infection index and in addition it induced NO production twice as high than control at the highest concentrations tested ( Figure 2D). Cassamale et al [12] have demonstrated this compound as highly active against L. (L.) amazonensis promastigote forms (IC 50 = 7.2 µM), and this suggests its direct action on the parasite. On the other hand, position isomer 18 (IC 50 = 29.8 µM, Table 1) was less active than 19, indicating the role of minor structural differences on the antileishmanial activity of these compounds.…”

“…6 has induced an increased production of nitric oxide (NO) compared to untreated infected cells (control) (Figure 2A). Thus, NO production may be suggested as the mechanism of leishmanicidal action, especially because 6 does not seem to have a direct action on L. (L.) amazonensis once it was proven inactive on promastigote forms [12]. The other compounds from trimethoxy series (with substituents on ring A) were active (11) and moderately active (15 and 18), but less selective, with important cytotoxicity on mammalian cells Treatment with compound 6 had significantly decreased the infection index at the concentration of 6.25 µg·mL −1 , reaching 98.6% reduction (p < 0.0001) at the concentration of 50 µg·mL −1 ( Figure 1A).…”

“…6 has induced an increased production of nitric oxide (NO) compared to untreated infected cells (control) (Figure 2A). Thus, NO production may be suggested as the mechanism of leishmanicidal action, especially because 6 does not seem to have a direct action on L. (L.) amazonensis once it was proven inactive on promastigote forms [12].…”

“…Cassamale et al [12] have synthetized a series of triazole derivatives from the tetrahydrofuran neolignans veraguensin 1, grandisin 2, and machilin G 3. These compounds have been considered important scaffolds in molecular modification studies due to their antileishmanial and antichagasic activities [13][14][15][16].…”