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

• Published in: Bioorganic & medicinal chemistry letters 2015-03, Vol.25 (6), p.1292-1296
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; BASIC BIOLOGICAL SCIENCES; Benzimidazole scaffold; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Binding Sites; Catalytic Domain; Crystallography, X-Ray; Enoyl reductase; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - antagonists & inhibitors; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - metabolism; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Escherichia coli - drug effects; F. tularensis; FabI inhibitor; Francisella tularensis - drug effects; Francisella tularensis - enzymology; Kinetics; Methicillin-Resistant Staphylococcus aureus - drug effects; Microbial Sensitivity Tests; Molecular Dynamics Simulation; MRSA; S. aureus; Staphylococcus aureus - drug effects; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.01.048

[Display omitted] 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.