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

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Authors: Mehboob, S; Song, J.; Hevener, K. E.; Su, P. C.; Boci, T.; Brubaker, L; Truong, L.; Mistry, T.; Deng, J; Cook, J. L.; Santarsiero, B. D.; Ghosh, A. K.; Johnson, M. E.
Article Title: Structural and biological evaluation of a novel series of benzimidazole inhibitors of Francisella tularensis enoyl-ACP reductase (FabI)
Abstract: 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.
Journal Title: Bioorganic medicinal chemistry letters
Volume: 25
Issue: 6
ISSN: 1464-3405; 0960-894X
Publisher: Unknown  
Journal Place: England
Date Published: 2015
Start Page: 1292
End Page: 1296
Language: eng
DOI/URL:

10.1016/j.bmcl.2015.01.048
Notes: LR: 20150305; CI: Published by Elsevier Ltd.; GR: R41 AI110090/AI/NIAID NIH HHS/United States; GR: U01 AI077949/AI/NIAID NIH HHS/United States; JID: 9107377; NIHMS662919; OID: NLM: NIHMS662919 [Available on 03/15/16]; OID: NLM: PMC4348352 [Available on 03/15/16]; OTO: NOTNLM; PMCR: 2016/03/15 00:00; 2014/12/02 [received]; 2015/01/19 [revised]; 2015/01/20 [accepted]; 2015/01/29 [aheadofprint]; ppublish