Structural and biological evaluation of a novel series of benzimidazole inhibitors of Francisella tularensis enoyl-ACP reductase (FabI)
- Univ. of Illinois, Chicago, IL (United States). Center for Pharmaceutical Biotechnology; Novalex Therapeutics, Chicago, IL (United States)
- Purdue Univ., West Lafayette, IN (United States). Dept. of Chemistry and Dept. of Medicinal Chemistry
- Univ. of Illinois, Chicago, IL (United States). Center for Pharmaceutical Biotechnology
- Loyola Univ. Chicago, Maywood, IL (United States). Division of Infectious Diseases; Edward Hines Jr. VA Hospital, Hines, IL (United States)
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. In the bacterial FASII pathway we found it 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. Furthermore, 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). Finally, 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.
- Research Organization:
- Univ. of Illinois, Chicago, IL (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)
- Grant/Contract Number:
- AC02-06CH11357; U01-AI077949; R41AI110090; UL1TR000050; P41-GM103311; 085P1000817
- OSTI ID:
- 1344120
- Alternate ID(s):
- OSTI ID: 1252342
- Journal Information:
- Bioorganic and Medicinal Chemistry Letters, Vol. 25, Issue 6; ISSN 0960-894X
- Publisher:
- ElsevierCopyright Statement
- Country of Publication:
- United States
- Language:
- English
Web of Science
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