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Design and synthesis of potent inhibitors of bc1 complex based on natural product neopeltolide.
Bioorganic & Medicinal Chemistry Letters ( IF 2.7 ) Pub Date : 2020-06-08 , DOI: 10.1016/j.bmcl.2020.127324
Mao-Qian Xiong 1 , Tao Chen 1 , Yu-Xia Wang 1 , Xiao-Lei Zhu 1 , Guang-Fu Yang 2
Affiliation  

Neopeltolide, a natural product isolated from deep-water sponge specimen of the family neopeltidae, has been proven to be a novel inhibitor of cytochrome bc1. In this study, a series of neopeltolide derivatives was designed by replacing the 14-membered macrolactone with indole ring and confirmed by 1H NMR, 13C NMR, and HRMS. Based on the binding mode of 12h with bc1 complex, the IC50 values of compounds 16a-f (ranging from 0.70 to 1.46 μM) were improved significantly than the ester derivatives 12a-u by replacing the ester with amide linker. Subsequently, the molecular docking results indicated that compound 16e could form a π-π interaction with Phe274 and two H-bonds with Glu271 and His161 and the latter H-bond was found to account for its high activity. The present work accelerates the discovery of novel bc1 complex inhibitors to deal with the resistance that the existing bc1 complex inhibitors are facing and provides a valuable idea for the design of new fungicides.



中文翻译:

设计和合成基于天然产物新象草内酯的bc1复合物有效抑制剂。

Neopeltolide是从新科科的深水海绵标本中分离出的天然产物,已被证明是细胞色素bc 1的新型抑制剂。在这项研究中,通过用吲哚环取代14元大内酯来设计一系列新pelolidelide衍生物,并通过1 H NMR,13 C NMR和HRMS证实。基于12hbc 1配合物的结合模式,化合物16a-f的IC 50值(范围从0.70至1.46μM)比酯衍生物12a-u显着提高通过用酰胺连接基取代酯。随后,分子对接结果表明化合物16e可与Phe274形成π-π相互作用,并与Glu271和His161形成两个H键,并且发现后者的H键是其高活性的原因。本工作加快了新型bc 1复合抑制剂的发现,以解决现有bc 1复合抑制剂面临的抗药性,并为设计新的杀菌剂提供了有价值的想法。

更新日期:2020-06-27
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