Abstract：
The design, synthesis, and biological evaluation of a novel series of HIV-1 protease inhibitors containing pyrrolidines with diverse linkers as the P2 ligands and various aromatic derivatives as the P2\' ligands were described. A number of inhibitors demonstrated potent efficacy in both enzyme and cellular assays, as well as relatively low cytotoxicity. In particular, inhibitor 34b with a (R)-pyrrolidine-3-carboxamide P2 ligand and a 4-hydroxyphenyl P2\' ligand displayed exceptional enzyme inhibitory activity with an IC50 value of 0.32 nM. Furthermore, 34b also exhibited robust antiviral activity against both wild-type HIV-1 and drug-resistant variant with low micromolar EC50 values. In addition, the molecular modelling studies revealed the extensive interactions between inhibitor 34b and the backbone residues of both wild-type and drug-resistant HIV-1 protease. These results suggested the feasibility of utilizing pyrrolidine derivatives as the P2 ligands and provided valuable information for further design and optimization of highly potent HIV-1 protease inhibitors.
摘要：
设计，合成，描述了一系列新型的HIV-1蛋白酶抑制剂的生物学评估，这些抑制剂包含吡咯烷，具有多种接头作为P2配体和各种芳香族衍生物作为P2配体。许多抑制剂在酶和细胞测定中均显示出有效的功效，以及相对较低的细胞毒性。特别是,具有(R)-吡咯烷-3-甲酰胺P2配体和4-羟苯基P2配体的抑制剂34b表现出优异的酶抑制活性,IC50值为0.32nM。此外，图34b还表现出对野生型HIV-1和具有低微摩尔EC50值的耐药变体两者的强大抗病毒活性。此外,分子模型研究揭示了抑制剂34b与野生型和耐药性HIV-1蛋白酶的主链残基之间的广泛相互作用。这些结果表明利用吡咯烷衍生物作为P2配体的可行性,并为进一步设计和优化高效HIV-1蛋白酶抑制剂提供了有价值的信息。
