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

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.
 [1] ;  [2] ;  [3] ;  [3] ;  [3] ;  [3] ;  [3] ;  [3] ;  [4] ;  [4] ;  [3] ;  [2] ;  [1]
  1. Univ. of Illinois, Chicago, IL (United States). Center for Pharmaceutical Biotechnology; Novalex Therapeutics, Chicago, IL (United States)
  2. Purdue Univ., West Lafayette, IN (United States). Dept. of Chemistry and Dept. of Medicinal Chemistry
  3. Univ. of Illinois, Chicago, IL (United States). Center for Pharmaceutical Biotechnology
  4. Loyola Univ. Chicago, Maywood, IL (United States). Division of Infectious Diseases; Edward Hines Jr. VA Hospital, Hines, IL (United States)
Publication Date:
Grant/Contract Number:
AC02-06CH11357; U01-AI077949; R41AI110090; UL1TR000050; P41-GM103311; 085P1000817
Accepted Manuscript
Journal Name:
Bioorganic & Medicinal Chemistry Letters
Additional Journal Information:
Journal Volume: 25; Journal Issue: 6; Journal ID: ISSN 0960-894X
Research Org:
Univ. of Illinois, Chicago, IL (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Institutes of Health (NIH)
Country of Publication:
United States
59 BASIC BIOLOGICAL SCIENCES; Enoyl reductase; Benzimidazole scaffold; F. tularensis; FabI inhibitor; S. aureus; MRSA
OSTI Identifier:
Alternate Identifier(s):
OSTI ID: 1252342