LASQUIM - Laboratório de Síntese e Química Medicinal, FACFAN - Faculdade de Ciências Farmacêuticas, Alimentos e Nutrição, Universidade Federal do Mato Grosso do Sul, UFMS, Campo Grande, MS, Brazil.
Laboratorio de Parasitologia Humana, INBIO - Instituto de Biologia, Universidade Federal do Mato Grosso do Sul, Campo Grande, MS, Brazil.
Chem Biol Drug Des. 2019 Mar;93(3):313-324. doi: 10.1111/cbdd.13417. Epub 2018 Nov 25.
Using 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 against Trypanosoma cruzi, Leishmania (L.) amazonensis and Leishmania (V.) braziliensis. All compounds were selective for the Leishmania genus and inactive against T. cruzi. Isoxazole analogues showed a standard activity on both promastigotes of L. amazonensis and L. braziliensis. The most active compounds were 15, 16 and 19 with IC values of 2.0, 3.3 and 9.5 μM against L. amazonensis and IC values of 1.2, 2.1 and 6.4 μM on L. 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.
利用生物等排作为药物化学工具，通过 1,3-偶极环加成反应合成了 16 个 3,5-二芳基异恶唑类似物，包括四氢呋喃新木脂素 veraguensin、grandisin 和 machilin G，产率为 43%至 90%。对 Trypanosoma cruzi、Leishmania (L.) amazonensis 和 Leishmania (V.) braziliensis 进行了抗锥虫生物活性评估。所有化合物均对利什曼原虫属具有选择性，对 T. cruzi 无活性。异恶唑类似物对 L. amazonensis 和 L. braziliensis 的前鞭毛体均表现出标准活性。最活跃的化合物是 15、16 和 19，对 L. amazonensis 的 IC 值分别为 2.0、3.3 和 9.5 μM，对 L. braziliensis 的 IC 值分别为 1.2、2.1 和 6.4 μM。所有化合物均无细胞毒性，其细胞毒性（>250 μM）低于戊脒（78.9 μM）。关于构效关系（SAR），亚甲二氧基基团对前鞭毛体的抗利什曼原虫活性至关重要。用异恶唑核取代四氢呋喃核可提高抗利什曼原虫活性。
