Searching for Novel Inhibitors of the S. aureus NorA Efflux Pump: Synthesis and Biological Evaluation of the 3‐Phenyl‐1,4‐benzothiazine Analogues

Bacterial resistance to antimicrobial agents has become an increasingly serious health problem in recent years. Among the strategies by which resistance can be achieved, overexpression of efflux pumps such as NorA of Staphylococcus aureus leads to a sub‐lethal concentration of the antibacterial agent at the active site that in turn may predispose the organism to the development of high‐level target‐based resistance. With an aim to improve both the chemical stability and potency of our previously reported 3‐phenyl‐1,4‐benzothiazine NorA inhibitors, we replaced the benzothiazine core with different nuclei. None of the new synthesized compounds showed any appreciable intrinsic antibacterial activity, and, in particular, 2‐(3,4‐dimethoxyphenyl)quinoline (6 c) was able to decrease, in a concentration‐dependent manner, the ciprofloxacin MIC against the norA‐overexpressing strains S. aureus SA‐K2378 (norA++) and SA‐1199B (norA+/A116E GrlA).

[1]  G. Kaatz,et al.  Pharmacophore-Based Repositioning of Approved Drugs as Novel Staphylococcus aureus NorA Efflux Pump Inhibitors. , 2017, Journal of medicinal chemistry.

[2]  L. Goracci,et al.  Indole Based Weapons to Fight Antibiotic Resistance: A Structure-Activity Relationship Study. , 2016, Journal of medicinal chemistry.

[3]  John J. Irwin,et al.  ZINC 15 – Ligand Discovery for Everyone , 2015, J. Chem. Inf. Model..

[4]  F. Bucar,et al.  Plant derived inhibitors of bacterial efflux pumps: an update , 2015, Phytochemistry Reviews.

[5]  Aurélien Lesnard,et al.  Boronic species as promising inhibitors of the Staphylococcus aureus NorA efflux pump: study of 6-substituted pyridine-3-boronic acid derivatives. , 2015, European journal of medicinal chemistry.

[6]  Aurélien Lesnard,et al.  First identification of boronic species as novel potential inhibitors of the Staphylococcus aureus NorA efflux pump. , 2014, Journal of medicinal chemistry.

[7]  G. Kaatz,et al.  Re-evolution of the 2-phenylquinolines: ligand-based design, synthesis, and biological evaluation of a potent new class of Staphylococcus aureus NorA efflux pump inhibitors to combat antimicrobial resistance. , 2013, Journal of medicinal chemistry.

[8]  J. Handzlik,et al.  Recent Advances in Multi-Drug Resistance (MDR) Efflux Pump Inhibitors of Gram-Positive Bacteria S. aureus , 2013, Antibiotics.

[9]  N. T. Patil,et al.  Enantioselective cooperative triple catalysis: unique roles of Au(I)/amine/chiral Brønsted acid catalysts in the addition/cycloisomerization/transfer hydrogenation cascade. , 2013, Chemical communications.

[10]  A. Oliver,et al.  High β-Lactamase Levels Change the Pharmacodynamics of β-Lactam Antibiotics in Pseudomonas aeruginosa Biofilms , 2012, Antimicrobial Agents and Chemotherapy.

[11]  M. Otto.  MRSA virulence and spread , 2012, Cellular microbiology.

[12]  G. Kaatz,et al.  Searching for innovative quinolone-like scaffolds: synthesis and biological evaluation of 2,1-benzothiazine 2,2-dioxide derivatives , 2012 .

[13]  K. Varani,et al.  7-Oxo-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamides as selective CB(2) cannabinoid receptor ligands: structural investigations around a novel class of full agonists. , 2012, Journal of medicinal chemistry.

[14]  Xiaomei Zhang,et al.  Lewis Base Organocatalyzed Enantioselective Hydrosilylation of 1,4-Benzoxazines , 2012, Synlett.

[15]  E. Carosati,et al.  Pyrazolo[4,3-c][1,2]benzothiazines 5,5-dioxide: a promising new class of Staphylococcus aureus NorA efflux pump inhibitors. , 2012, Journal of medicinal chemistry.

[16]  G. Cruciani,et al.  Ligand Promiscuity between the Efflux Pumps Human P-Glycoprotein and S. aureus NorA. , 2012, ACS medicinal chemistry letters.

[17]  B. Schmidt,et al.  Oxidative Homologation of Aldehydes to α‐Ketoaldehydes by using Iodoform, o‐Iodoxybenzoic Acid, and Dimethyl Sulf­oxide , 2012 .

[18]  G. Kaatz,et al.  Evolution from a natural flavones nucleus to obtain 2-(4-Propoxyphenyl)quinoline derivatives as potent inhibitors of the S. aureus NorA efflux pump. , 2011, Journal of medicinal chemistry.

[19]  Stefano Sabatini,et al.  Discovery of novel inhibitors of the NorA multidrug transporter of Staphylococcus aureus. , 2011, Journal of medicinal chemistry.

[20]  G. Kaatz,et al.  Ethidium Bromide MIC Screening for Enhanced Efflux Pump Gene Expression or Efflux Activity in Staphylococcus aureus , 2010, Antimicrobial Agents and Chemotherapy.

[21]  M. Rueping,et al.  Asymmetric Brønsted acid catalysis in aqueous solution , 2010 .

[22]  Lee H. Harrison,et al.  Health care-associated invasive MRSA infections, 2005-2008. , 2010, JAMA.

[23]  Ling Zhang,et al.  Efflux Pump Inhibitors: A Strategy to Combat P‐Glycoprotein and the NorA Multidrug Resistance Pump , 2010, ChemMedChem.

[24]  E. Carosati,et al.  From 6-aminoquinolone antibacterials to 6-amino-7-thiopyranopyridinylquinolone ethyl esters as inhibitors of Staphylococcus aureus multidrug efflux pumps. , 2010, Journal of medicinal chemistry.

[25]  M. Rueping,et al.  The first general, efficient and highly enantioselective reduction of quinoxalines and quinoxalinones. , 2010, Chemistry.

[26]  J. Baell,et al.  New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. , 2010, Journal of medicinal chemistry.

[27]  H. Nikaido,et al.  Efflux-Mediated Drug Resistance in Bacteria , 2009, Drugs.

[28]  F. Verpoort,et al.  Base-mediated synthesis of quinolines: an unexpected cyclization reaction between 2-aminobenzylalcohol and ketones , 2008 .

[29]  A. Hidrón,et al.  Antimicrobial-Resistant Pathogens Associated With Healthcare-Associated Infections: Annual Summary of Data Reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006–2007 , 2008, Infection Control & Hospital Epidemiology.

[30]  Viktoria Hancock,et al.  Inactivation of Efflux Pumps Abolishes Bacterial Biofilm Formation , 2008, Applied and Environmental Microbiology.

[31]  D. Payne.  Desperately Seeking New Antibiotics , 2008, Science.

[32]  Joseph I. Ambrus,et al.  Structure-activity relationships of 2-aryl-1H-indole inhibitors of the NorA efflux pump in Staphylococcus aureus. , 2008, Bioorganic & medicinal chemistry letters.

[33]  Gary Taubes,et al.  The Bacteria Fight Back , 2008, Science.

[34]  G. Kaatz,et al.  From phenothiazine to 3-phenyl-1,4-benzothiazine derivatives as inhibitors of the Staphylococcus aureus NorA multidrug efflux pump. , 2008, Journal of medicinal chemistry.

[35]  S. Zaher.  Clinical Infectious Disease , 2008 .

[36]  Roberta B Carey,et al.  Invasive methicillin-resistant Staphylococcus aureus infections in the United States. , 2007, JAMA.

[37]  A. Shorr.  Epidemiology of staphylococcal resistance. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[38]  L. Piddock,et al.  Bacterial efflux pump inhibitors from natural sources. , 2007, The Journal of antimicrobial chemotherapy.

[39]  Jean-Marie Pagès,et al.  Antibiotic efflux pumps in Gram-negative bacteria: the inhibitor response strategy. , 2007, The Journal of antimicrobial chemotherapy.

[40]  J. Weber.  Community-associated methicillin-resistant Staphylococcus aureus. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[41]  W. Jarvis,et al.  Has methicillin-resistant Staphylococcus aureus stopped spreading in intensive care units? , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[42]  C. Cho,et al.  Consecutive isomerization and cyclization of 3-(2-aminophenyl)-1-arylprop-2-yn-1-ols leading to 2-arylquinolines in the presence of potassium hydroxide , 2004 .

[43]  S. Gibbons.  Anti-staphylococcal plant natural products. , 2004, Natural product reports.

[44]  H. Nikaido.  Molecular Basis of Bacterial Outer Membrane Permeability Revisited , 2003, Microbiology and Molecular Biology Reviews.

[45]  Alessandra Napolitano,et al.  1,4-benzothiazines as key intermediates in the biosynthesis of red hair pigment pheomelanins. , 2003, Pigment cell research.

[46]  G. Kaatz,et al.  Phenylpiperidine selective serotonin reuptake inhibitors interfere with multidrug efflux pump activity in Staphylococcus aureus. , 2003, International journal of antimicrobial agents.

[47]  J. Ruiz.  Mechanisms of resistance to quinolones: target alterations, decreased accumulation and DNA gyrase protection. , 2003, The Journal of antimicrobial chemotherapy.

[48]  G. Kaatz,et al.  Phenothiazines and Thioxanthenes Inhibit Multidrug Efflux Pump Activity in Staphylococcus aureus , 2003, Antimicrobial Agents and Chemotherapy.

[49]  R. SanMartin,et al.  A Simple Route to New Phenanthro‐ and Phenanthroid‐Fused Thiazoles by a PIFA‐Mediated (Hetero)biaryl Coupling Reaction , 2002 .

[50]  Claude Carbón.  MRSA and MRSE: is there an answer? , 2000, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[51]  G. Wright,et al.  Resisting resistance: new chemical strategies for battling superbugs. , 2000, Chemistry & biology.

[52]  M. Wahiduzzaman,et al.  Evidence for the Existence of a Multidrug Efflux Transporter Distinct from NorA in Staphylococcus aureus , 2000, Antimicrobial Agents and Chemotherapy.

[53]  G. Fabrizi,et al.  The Palladium-Catalyzed Transfer Hydrogenation/Heterocyclization of β-(2-Aminophenyl)-α,β-ynones. An Approach to 2-Aryl- and 2-Vinylquinolines , 1999 .

[54]  G. Kaatz,et al.  Effects of NorA Inhibitors on In Vitro Antibacterial Activities and Postantibiotic Effects of Levofloxacin, Ciprofloxacin, and Norfloxacin in Genetically Related Strains ofStaphylococcus aureus , 1999, Antimicrobial Agents and Chemotherapy.

[55]  J. Verhoef,et al.  The effect of reserpine, an inhibitor of multidrug efflux pumps, on the in-vitro activities of ciprofloxacin, sparfloxacin and moxifloxacin against clinical isolates of Staphylococcus aureus. , 1998, The Journal of antimicrobial chemotherapy.

[56]  K. Bush,et al.  Bacterial enzymatic resistance: β-lactamases and aminoglycoside-modifying enzymes , 1998 .

[57]  G. Kaatz,et al.  Mechanisms of fluoroquinolone resistance in genetically related strains of Staphylococcus aureus , 1997, Antimicrobial agents and chemotherapy.

[58]  R. Wise,et al.  The effect of reserpine, an inhibitor of multi-drug efflux pumps, on the in-vitro susceptibilities of fluoroquinolone-resistant strains of Streptococcus pneumoniae to norfloxacin. , 1997, The Journal of antimicrobial chemotherapy.

[59]  S. Cenini,et al.  Intramolecular amination catalysed by ruthenium and palladium. Synthesis of 2-acyl indoles and 2-aryl quinolines by carbonylation of 2-nitrochalcones , 1996 .

[60]  S. Schuldiner,et al.  Mutants of the Bacillus subtilis multidrug transporter Bmr with altered sensitivity to the antihypertensive alkaloid reserpine. , 1993, The Journal of biological chemistry.

[61]  K. Entian,et al.  Genetic analysis of epidermin biosynthetic genes and epidermin-negative mutants of Staphylococcus epidermidis. , 1992, European journal of biochemistry.

[62]  L. Reimer,et al.  Antibiotics in laboratory medicine , 1987 .

[63]  G. Sabitha,et al.  Synthesis of 3-Arylcoumarins, 2-Aroylbenzofurans and 3-Aryl-2H-1,4-benzoazines Under Phase-Transfer Catalysis Conditions , 1987 .

[64]  C. Iijima,et al.  Quinoxalines. XXII. Aryl Migration of 2-Aroylquinoxalines to 2-Arylquinoxalines , 1985 .

[65]  P. Battistoni,et al.  A GENERAL METHOD FOR THE SYNTHESIS OF 3-PHENYL-2H-1,4-BENZOXAZINES AND 3-PHENYL-2H-3,4-DIHYDRO-1,4-BENZOXAZINES , 1979 .

[66]  W. Ried,et al.  Reaktionen mit Cyclobutendionen, XL. Ringöffnungsreaktionen des 3,4-Diphenyl-3-cyclobuten-1,2-dions mit dinucleophilen Agenzien , 1976 .

[67]  S W B Newsom,et al.  Antimicrobial Agents and Chemotherapy—1967 , 1966 .

[68]  W. Horton,et al.  Seven-membered Ring Compounds. VII.1 7-Acetamidobenzosuberone and α-Amino-γ-3,4,5-trimethoxyphenylbutyric Acid , 1954 .

[69]  J. H. Boyer,et al.  Azidocarbonyl Compounds. II. The Pyrolysis of α-Azidocarbonyl Compounds1a , 1953 .

[70]  Dl Hoyert,et al.  National Vital Statistics Reports NCHS.pdf , 2012 .

[71]  Hiroshi Nikaido,et al.  Efflux-Mediated Drug Resistance in Bacteria , 2012, Drugs.

[72]  J. Bartlett,et al.  Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[73]  S. Leeder.  World Health OrganizationWHO Library Cataloguing-in-Publication Data , 2004 .

[74]  Mary Jane Ferraro,et al.  Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically : approved standard , 2000 .

[75]  J. Waitz.  Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically , 1990 .

[76]  S. Goldstein,et al.  2-Substituted 1,2,3,4-Tetrahydroquinolines from Quinoline , 1989 .

[77]  S. Murata,et al.  Hydrogenation and hydrosilylation of quinoxaline by homogeneous rhodium catalysts , 1987 .

[78]  P. Battistoni,et al.  3-phenyl-2H-1,4-benzoxazine-4-oxides—I : Synthesis and reduction , 1979 .

[79]  G. Prota,et al.  Oxidative behaviour of 3-aryl-2H-1,4-benzoxazines , 1976 .

[80]  G. Lindstedt,et al.  Attempts to Synthesize alpha-(3,4-Dimethoxyphenyl)glycerol Derivatives. , 1950 .

[81]  F. M. Hamer,et al.  19. Thiazinocyanines. Part I. Carbocyanines containing the 2 : 4-benzthiazine nucleus , 1942 .