Effect of isoxazole derivatives of tetrahydrofuran neolignans on intracellular amastigotes of Leishmania (Leishmania) amazonensis: A structure-activity relationship (SAR) comparative study with triazole-neolignan-based compounds.

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 IC50 values ranging from 0.4 to 25 mu M. The most active analogues were 4 ', 14 ', 15 ', and 18 ', with IC50 values of 0.9, 0.4, 0.7, and 1.4 mu M, 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.