10.1021/ol400150z r 2013 American Chemical Society Published on Web 03/05/2013 ORGANIC LETTERS 2013 Vol. 15, No. 6 1234–1237 Development of Quinoline-Based Disruptors of Biofilm Formation Against Vibrio cholerae Brian Le  on, † Jiunn C. N. Fong, ‡ Kelly C. Peach, † Weng Ruh Wong, † Fitnat H. Yildiz, ‡ and Roger G. Linington* ,† Department of Chemistry and Biochemistry and Department of Microbiology and Environmental Toxicology, University of California, Santa Cruz, 1156 High Street, Santa Cruz, California 95064, United States rliningt@ucsc.edu Received January 17, 2013 ABSTRACT Biofilm formation is a major cause of bacterial persistence in nosocomial infections, leading to extended treatment times and increased rates of morbidity and mortality. Despite this, there are currently no biofilm inhibitors approved for clinical use. The synthesis and biological evaluation of a library of amino alcohol quinolines as lead compounds for the disruption of biofilm formation in Vibrio cholerae is now reported. Application of selective metalÀhalogen exchange chemistry installed both stereocenters in one step, to afford a simpler scaffold than the initial lead molecule, with an EC 50 < 10 μM. Bacterial biofilms are surface-associated bacterial as- semblages containing microbial cells encased in an extra- cellular matrix of exopolysaccharides, proteins and DNA. Biofilm formation is increasingly being recognized as a major component of bacterial pathogenesis, with current estimates suggesting that up to 75% of pathogenic micro- bial infections are biofilm mediated. 1 This is considered to be a significant contributor to the development and persis- tence of nosocomial (hospital acquired) infections. Biofilm- associated infections are particularly difficult to clear because cells within the matrix can enter a latent state that reduces their susceptibility to traditional antibiotics. This results in a significant increase in bacterial persistence, leading to a concomitant increase in antibiotic treatment times, and a subsequent acceleration in the development of drug-resistance. 2 Despite detailed investigation of several compound series in recent years, 3 there are still no com- mercially available biofilm inhibitors that are approved for clinical use. To discover new therapeutic options for biofilm-associated infections, we recently developed an image-based high content screening platform for the discovery of bio- film inhibitors in the model organism Vibrio cholerae. 4 Previous screening of a 3080-member small molecule library from the National Cancer Institute (NCI) revealed 29 compounds with the ability to selectively disrupt biofilm formation. Of these, two (NSC 13480, 3, EC 50 = 11.1 μM; NSC 305787, 4, EC 50 = 10.6 μM) were closely related, possessing a 2,4-disubstituted quinoline core and a β-amino alcohol motif (Figure 1). Many FDA approved drugs contain this privileged quinoline ring structure, 5 † Department of Chemistry and Biochemistry. ‡ Department of Microbiology and Environmental Toxicology. (1) Richards, J.; Melander, C. ChemBioChem 2009, 10, 2287–2294. (2) Davies, D. Nat. Rev. Drug Discovery 2003, 2, 114–122. (3) Worthington, R. J.; Richards, J. J.; Melander, C. Org. Biomol. Chem. 2012, 10, 7457–7474. (4) Peach, K. C.; Bray, W. M.; Shikuma, N. J.; Gassner, N. C.; Lokey, R. S.; Yildiz, F. H.; Linington, R. G. Mol. BioSyst. 2011, 7, 1176– 1184. (5) Solomon, V. R.; Lee, H. Curr. Med. Chem. 2011, 18, 1488–1508. Downloaded via UNIV OF CALIFORNIA SAN DIEGO on August 23, 2018 at 04:34:47 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.