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

Title: 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. ^[1]

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.

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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

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Cited by: 16 works

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References (17)

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Discovery of a Novel and Potent Class of F. tularensis Enoyl-Reductase (FabI) Inhibitors by Molecular Shape and Electrostatic Matching Hevener, Kirk E.; Mehboob, Shahila; Su, Pin-Chih Journal of Medicinal Chemistry, Vol. 55, Issue 1 https://doi.org/10.1021/jm201168g	journal	December 2011
Structural and Enzymatic Analyses Reveal the Binding Mode of a Novel Series of Francisella tularensis Enoyl Reductase (FabI) Inhibitors Mehboob, Shahila; Hevener, Kirk E.; Truong, Kent Journal of Medicinal Chemistry, Vol. 55, Issue 12 https://doi.org/10.1021/jm300489v	journal	June 2012
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Cited By (5)

Evaluating thermodynamic integration performance of the new amber molecular dynamics package and assess potential halogen bonds of enoyl-ACP reductase (FabI) benzimidazole inhibitors: TI Performance of the New Amber MD Package Su, Pin-Chih; Johnson, Michael E. Journal of Computational Chemistry, Vol. 37, Issue 9 https://doi.org/10.1002/jcc.24274	journal	December 2015
Comparison of radii sets, entropy, QM methods, and sampling on MM-PBSA, MM-GBSA, and QM/MM-GBSA ligand binding energies of F . tularensis enoyl-ACP reductase (FabI) Su, Pin-Chih; Tsai, Cheng-Chieh; Mehboob, Shahila Journal of Computational Chemistry, Vol. 36, Issue 25 https://doi.org/10.1002/jcc.24011	journal	July 2015
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
Antimicrobial potential of 1H-benzo[d]imidazole scaffold: a review Tahlan, Sumit; Kumar, Sanjiv; Narasimhan, Balasubramanian BMC Chemistry, Vol. 13, Issue 1 https://doi.org/10.1186/s13065-019-0521-y	journal	February 2019
Design and Synthesis of Benzimidazole-Chalcone Derivatives as Potential Anticancer Agents Molecules, Vol. 24, Issue 18 https://doi.org/10.3390/molecules24183259	journal	September 2019

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

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

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