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

Mehboob, Shahila; Song, Jinhua; Hevener, Kirk E.; Su, Pin-Chih; Boci, Teuta; Brubaker, Libby; Truong, Lena; Mistry, Tina; Deng, Jiangping; Cook, James L.; Santarsiero, Bernard D.; Ghosh, Arun K.; Johnson, Michael E.

doi:10.1016/j.bmcl.2015.01.048

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

Journal Article · Thu Jan 29 00:00:00 EST 2015 · Bioorganic and Medicinal Chemistry Letters

DOI:https://doi.org/10.1016/j.bmcl.2015.01.048· OSTI ID:1344120

Mehboob, Shahila ^[1]; Song, Jinhua ^[2]; Hevener, Kirk E. ^[3]; Su, Pin-Chih ^[3]; Boci, Teuta ^[3]; Brubaker, Libby ^[3]; Truong, Lena ^[3]; Mistry, Tina ^[3]; Deng, Jiangping ^[4]; Cook, James L. ^[4]; Santarsiero, Bernard D. ^[3]; Ghosh, Arun K. ^[2]; Johnson, Michael E. ^[5]

Univ. of Illinois, Chicago, IL (United States). Center for Pharmaceutical Biotechnology; Novalex Therapeutics, Chicago, IL (United States); Office of Scientific and Technical Information (OSTI)
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)
Univ. of Illinois, Chicago, IL (United States). Center for Pharmaceutical Biotechnology; Novalex Therapeutics, Chicago, 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.

View Accepted Manuscript (DOE)

Research Organization:: Univ. of Illinois, Chicago, IL (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1344120

Alternate ID(s):: OSTI ID: 1252342
OSTI ID: 1498354

Journal Information:: Bioorganic and Medicinal Chemistry Letters, Journal Name: Bioorganic and Medicinal Chemistry Letters Journal Issue: 6 Vol. 25; ISSN 0960-894X

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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Structure‐based drug design and in vitro testing reveal new inhibitors of enoyl‐acyl carrier protein reductases Ghattas, Mohammad A.; Eissa, Nermin A.; Tessaro, Francesca Chemical Biology & Drug Design https://doi.org/10.1111/cbdd.13536	journal	June 2019

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59 BASIC BIOLOGICAL SCIENCES
Benzimidazole scaffold
Enoyl reductase
F. tularensis
FabI inhibitor
MRSA
S. aureus

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