Small molecule fusion inhibitors: Design, synthesis and biological evaluation of (Z)-3-(5-(3-benzyl-4-oxo-2-thioxothiazolidinylidene)methyl)-N-(3-carboxy-4-hydroxy)phenyl-2,5-dimethylpyrroles and related derivatives targeting HIV-1 gp41
Small molecule fusion inhibitors: Design, synthesis and biological evaluation of (Z)-3-(5-(3-benzyl-4-oxo-2-thioxothiazolidinylidene)methyl)-N-(3-carboxy-4-hydroxy)phenyl-2,5-dimethylpyrroles and related derivatives targeting HIV-1 gp41
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DOI：
10.1016/j.bmc.2013.04.046
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发表时间：
2013-12-01
影响因子：
3.5
通讯作者：
Xie, Lan
中科院分区：
文献类型：
--
作者：
He, Xiao-Yang;Lu, Lu;Xie, Lan
通过支架延伸策略，设计、合成了一系列具有线性多芳环骨架的(Z)-3-(5-（3-苄基-4-氧-2-硫氧噻唑基）甲基- n -（3-羧基-4-羟基）苯基-2,5-二甲基吡咯及其衍生物，并在HIV-1 gp41和细胞检测中进行了评估。其中活性最强的化合物12e、12g和12k在罗丹宁环(C)和苯基环(D)之间有一个单碳连接体（n = 1），对MT-2细胞中gp41 6-HB形成和HIV-1复制的IC50值分别为1.8-2.6 μ M和0.3-1.5 μ M，显示出非常有希望的抑制效力。此外，它们对t20敏感菌株和耐药菌株几乎同样有效。相关的SAR研究和分子模拟结果为进一步开发一类新的靶向HIV-1 gp41的非肽小分子融合抑制剂提供了潜力。(C) 2013 Elsevier Ltd.版权所有。
By a scaffold elongation strategy, a series of (Z)-3-(5-(3-benzyl-4-oxo-2-thioxothiazolidinylidene)methyl)-N-(3-carboxy-4-hydroxy)phenyl-2,5-dimethylpyrroles and related derivatives with a linear multi-aromatic-ring skeleton were designed, synthesized, and evaluated in HIV-1 gp41 and cellular assays. Among them, the most active compounds, 12e, 12g, and 12k with a one-carbon linker (n = 1) between the rhodanine (C) and phenyl (D) rings, exhibited very promising inhibitory potency with IC50 values of 1.8-2.6 mu M and EC50 values of 0.3-1.5 mu M against gp41 6-HB formation and HIV-1 replication in MT-2 cells, respectively. Additionally, they were almost equally effective against both T20-sensitive and resistant strains. The related SAR studies and molecular modeling results provided potential for further developing a new class of non-peptide small molecular fusion inhibitors targeting the HIV-1 gp41. (C) 2013 Elsevier Ltd. All rights reserved.