Conformation-guided analogue design identifies potential antimalarial compounds through inhibition of mitochondrial respiration.
Conformation-guided analogue design identifies potential antimalarial compounds through inhibition of mitochondrial respiration.
复制标题
构象引导的类似物设计通过抑制线粒体呼吸来识别潜在的抗疟化合物。
DOI：
10.1039/c8ob01257a
复制
发表时间：
2018
影响因子：
3.2
通讯作者：
Taylor,RichardE
中科院分区：
文献类型：
--
作者：
Larsen,ErikM;Chang,Chia-Fu;Sakata-Kato,Tomoyo;Arico,JosephW;Lombardo,VinceM;Wirth,DyannF;Taylor,RichardE
合成的2-甲基取代的类似物的天然产物，neopeltolide，在努力分析的重要性，分子构象和配体靶相互作用的生物活性。通过后期中间体的高度非对映选择性酯烯醇化物烷基化来引入甲基取代。恶唑侧链的偶联通过全合成提供2-甲基-新戊内酯和合成的新戊内酯。通过计算机建模和NMR研究表明，取代保持其生物活性母体化合物的构象偏好。这两种化合物通过抑制恶性疟原虫的线粒体呼吸而显示出潜在的抗疟化合物。
The synthesis of a 2-methyl-substituted analogue of the natural product, neopeltolide, is reported in an effort to analyze the importance of molecular conformation and ligand–target interactions in relation to biological activity. The methyl substitution was incorporated via highly diastereoselective ester enolate alkylation of a late-stage intermediate. Coupling of the oxazole sidechain provided 2-methyl-neopeltolide and synthetic neopeltolide via total synthesis. The substitution was shown to maintain the conformational preferences of its biologically active parent compound through computer modeling and NMR studies. Both compounds were shown to be potential antimalarial compounds through the inhibition of mitochondrial respiration in P. falciparum parasites.