Structural and biological evaluation of a novel series of benzimidazole inhibitors of Francisella tularensis enoyl-ACP reductase (FabI)

被引:17
作者
Mehboob, Shahila [1 ,2 ]
Song, Jinhua [3 ,4 ]
Hevener, Kirk E. [1 ]
Su, Pin-Chih [1 ]
Boci, Teuta [1 ]
Brubaker, Libby [1 ]
Truong, Lena [1 ]
Mistry, Tina [1 ]
Deng, Jiangping [5 ,6 ]
Cook, James L. [5 ,6 ]
Santarsiero, Bernard D. [1 ]
Ghosh, Arun K. [3 ,4 ]
Johnson, Michael E. [1 ,2 ]
机构
[1] Univ Illinois, Ctr Pharmaceut Biotechnol, Chicago, IL 60607 USA
[2] Novalex Therapeut, Chicago, IL 60612 USA
[3] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA
[4] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA
[5] Loyola Univ Chicago, Div Infect Dis, Maywood, IL 60153 USA
[6] Edward Hines Jr VA Hosp, Hines, IL 60141 USA
基金
美国国家卫生研究院;
关键词
Enoyl reductase; Benzimidazole scaffold; F; tularensis; FabI inhibitor; S; aureus; MRSA; CARRIER PROTEIN REDUCTASE; GRAM-POSITIVE PATHOGENS; FATTY-ACID SYNTHESIS; STAPHYLOCOCCUS-AUREUS; FASII PATHWAY; TULAREMIA; ESSENTIALITY; DERIVATIVES; DISCOVERY;
D O I
10.1016/j.bmcl.2015.01.048
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Francisella tularensis, the causative agent of tularemia, presents a significant biological threat and is a Category A priority pathogen due to its potential for weaponization. The bacterial FASII pathway is a viable target for the development of novel antibacterial agents treating Gram-negative infections. Here we report the advancement of a promising series of benzimidazole FabI (enoyl-ACP reductase) inhibitors to a second-generation using a systematic, structure-guided lead optimization strategy, and the determination of several co-crystal structures that confirm the binding mode of designed inhibitors. These compounds display an improved low nanomolar enzymatic activity as well as promising low microgram/mL antibacterial activity against both F. tularensis and Staphylococcus aureus and its methicillin-resistant strain (MRSA). The improvements in activity accompanying structural modifications lead to a better understanding of the relationship between the chemical structure and biological activity that encompasses both enzymatic and whole-cell activity. Published by Elsevier Ltd.
引用
收藏
页码:1292 / 1296
页数:5
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