title: Discovery and initial structure-activity relationships of N-benzyl tricyclic indolines as antibacterials for methicillin-resistant Staphylococcus aureus.
abstract: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most prevalent drug resistant bacteria. In 2012, over 11,000 fatalities in the United States were directly attributable to MRSA. In an effort to develop novel structural and mechanistic classes of antibacterial agents to fight against MRSA, we have optimized a hit compound, Of4, previously discovered in a screening campaign of a bio-inspired polycyclic indoline library previously developed in our lab. We took advantage of our concise and versatile synthetic strategy to conduct initial structure-activity relationship studies of Of4, and we now report the discovery of compound 4k as a more potent antibacterial agent against S. aureus. Compound 4k also displayed equivalent activity in four MRSA and a methicillin-susceptible strains while demonstrating an improved mammalian cytotoxicity profile compared to Of4. Interestingly, 4k shares the same tricyclic indoline core as Of1, a β-lactam-selective resistance-modifying agent, but harbors a distinct modification pattern conferring unique bioactivity. This phenomenon is reminiscent of many bioactive natural products.
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, United States.
authors.forename: P
authors.initials: P
authors.lastname: Michael Barbour
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, United States.
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Podoll
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, United States.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Marholz
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, United States. Electronic address: xiang.wang@colorado.edu.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D011083:Polycyclic Compounds / Q000737:chemistry*; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D018440:beta-Lactam Resistance / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D007211:Indoles; D011083:Polycyclic Compounds; C057812:indoline
keywords: Antibacterial; Gold catalysis; Indole alkaloid; MRSA; Polycyclic indoline