Design, Synthesis, and Structure-Activity Relationship of a Novel Series of 2-Aryl 5-(4-Oxo-3-phenethyl-2-thioxothiazolidinylidenemethyl)furans as HIV-1 Entry Inhibitors
Design, Synthesis, and Structure-Activity Relationship of a Novel Series of 2-Aryl 5-(4-Oxo-3-phenethyl-2-thioxothiazolidinylidenemethyl)furans as HIV-1 Entry Inhibitors
复制标题
DOI：
10.1021/jm900450n
复制
发表时间：
2009-12-10
影响因子：
7.3
通讯作者：
Debnath, Asim K.
中科院分区：
文献类型：
--
作者：
Katritzky, Alan R.;Tala, Srinivasa R.;Debnath, Asim K.
我们之前鉴定了两种针对 HIV-1 gp41 的小分子，即 N-(4-羧基-3-羟基)苯基-2,5-二甲基吡咯 12 (NB-2) 和 N-(3-羧基-4-氯)苯基吡咯 13 (NB-64)，它们能够在低微摩尔水平下抑制 HIV-1 感染。在分子对接分析的基础上，我们设计了一系列2-芳基5-(4-氧代-3-苯乙基-2-硫代噻唑烷亚甲基)呋喃。与12和13相比，这些化合物具有更大的分子尺寸（437-515 Da），并且可以在gp41 NHR三聚体的深层疏水口袋油中占据更多的空间。通过 Suzuki-Miyaura 交叉偶联和 Knoevenagel 缩合合成了 15 个 2-芳基 5-(4-氧代-3-苯乙基-2-硫代噻唑烷亚甲基)呋喃 (11a-o)，并测试了它们的抗 HIV-1 活性和对 MT-2 细胞的细胞毒性。我们发现所有 15 种化合物均具有改善的抗 HIV-1 活性，其中 3 种（11a、11b 和 11d）在 < 100 nM 范围内表现出对 HIB-1(IIIB) 和 94UG103 复制的抑制活性，比 12 和 13 强 20 倍以上，表明这些化合物可以作为开发新型小分子 HIV 融合抑制剂的先导化合物。
We previously identified two small molecules targeting the HIV-1 gp41, N-(4-carboxy-3-hydroxy)phenyl-2,5-dimethylpyrrole 12 (NB-2) and N-(3-carboxy-4-chloro)phenylpyrrole 13 (NB-64), that inhibit HIV-1 infection at low micromolar levels. Oil the basis of molecular docking analysis, we designed a series of 2-aryl 5-(4-oxo-3-phenethyl-2-thioxothiazolidinylidenemethyl)furans. Compared with 12 and 13, these compounds have bigger molecular size (437-515 Da) and could occupy more space in the deep hydrophobic pocket oil the gp41 NHR trimer. Fifteen 2-aryl 5-(4-oxo-3-phenethyl-2-thioxothiazolidinylidenemethyl)furans (11a-o) were synthesized by Suzuki-Miyaura cross-coupling followed by a Knoevenagel condensation and tested for their anti-HIV-1 activity and cytotoxicity on MT-2 cells. We found that all 15 compounds had improved anti-HIV-1 activity and 3 of them (11a, 11b, and 11d) exhibited inhibitory activity against replication of HIB-1(IIIB) and 94UG103 at < 100 nM range, more than 20-fold more potent than 12 and 13, suggesting that these Compounds can serve as leads for development of novel small molecule HIV fusion inhibitors.