LASQUIM - Laboratório de Síntese e Química Medicinal, Faculdade de Ciências Farmacêuticas, Alimentos e Nutrição, Universidade Federal de Mato Grosso do Sul, Campo Grande, Brazil.
Laboratório de Parasitologia Humana, Instituto de Biociências, Universidade Federal de Mato Grosso do Sul, Campo Grande, Brazil.
Chem Biol Drug Des. 2019 Dec;94(6):2004-2012. doi: 10.1111/cbdd.13609. Epub 2019 Sep 12.
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 values ranging from 0.4 to 25 μM. The most active analogues were 4', 14', 15', and 18', with IC 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.
先前，通过生物等排策略，从新木脂素化合物韦拉古辛、大根香叶素和马奇林 G 中衍生出异恶唑类似物，并具有不同的取代模式。这些化合物在莱什曼原虫（Leishmania）亚马逊亚种的细胞内无鞭毛体上进行了测试；衍生物对细胞内无鞭毛体表现出活性，IC 值范围为 0.4 至 25 μM。最活跃的类似物是 4'、14'、15'和 18'，IC 值分别为 0.9、0.4、0.7 和 1.4 μM，显示出高选择性指数（SI=277.0；625.0；178.5 和 357.1）。总体而言，异恶唑类似物不会诱导感染细胞产生一氧化氮（NO）；没有证据表明 NO 会影响抗利什曼原虫的作用机制，除了化合物 4'。作为取代基的三甲氧基似乎对抗利什曼原虫活性至关重要。SAR 研究表明，异恶唑化合物比具有相同取代模式的 1,2,3-三唑化合物更具活性，这表明生物等排策略在药物设计中的重要性。
