期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 25, 期 6, 页码 1292-1296出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2015.01.048
关键词
Enoyl reductase; Benzimidazole scaffold; F. tularensis; FabI inhibitor; S. aureus; MRSA
资金
- National Institutes of Health [U01-AI077949, R41AI110090]
- NIDCR, UIC College of Dentistry, MOST Program [5T32-DE018381]
- American Heart Association, the Mid-West Affiliate [13PRE14800030]
- UIC Center for Clinical and Translational Science through National Institutes of Health [UL1TR000050]
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]
- Michigan Technology Tri-Corridor [085P1000817]
- Michigan Economic Development Corporation [085P1000817]
- NIGMS [P41-GM103311]
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.
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