Design, synthesis and antitrypanosomatid activities of 3,5 ‐diaryl‐isoxazole analogues based on neolignans veraguensin, grandisin and machilin G

In this work, sixteen 3,5 ‐diaryl‐isoxazole analogues based on neolignans veraguensin, grandisin and machilin G were synthesized, and biological activity was evaluated againstL.  amazonensis, L. braziliensis andT.  cruzi. AbstractUsing 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 againstTrypanosoma cruzi, Leishmania (L.)amazonensis andLeishmania (V.)braziliensis. All compounds were selective for theLeishmania genus and inactive againstT.  cruzi. Isoxazole analogues showed a standard activity on both promastigotes ofL.  amazonensis andL.  braziliensis. The most active compounds were15, 16 and19 with IC50 values of 2.0, 3.3 and 9.5  μM againstL.  amazonensis and IC50 values of 1.2, 2.1 and 6.4  μM onL.  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.
Source: Chemical Biology and Drug Design - Category: Biology Authors: Tags: RESEARCH ARTICLE Source Type: research