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Fragment-to-Hit-to-Lead Discovery of a Novel Pyridylurea Scaffold of ATP Competitive Dual Targeting Type II Topoisomerase Inhibiting Antibacterial Agents.

Abstract

The discovery and optimization of a new class of bacterial topoisomerase (DNA gyrase and topoisomerase IV) inhibitors binding in the ATP domain is described. A fragment molecule, 1-ethyl-3-(2-pyridyl)urea, provided sufficiently potent enzyme inhibition (32 M) to prompt further analog work. Acids and acid isosteres were incorporated at the 5-pyridyl position of this fragment bridging to a key asparagine residue improving enzyme inhibition and leading to measurable antibacterial activity. A CF3-thiazole substituent at the 4-pyridyl position improved inhibitory potency due to a favorable lipophilic interaction. Promising antibacterial activity was seen versus the Gram-positive pathogens Staphylococcus aureus and Streptococcus pneumoniae and the Gram-negative pathogens Haemophilus influenzae and Moraxella catarrhalis. Precursor metabolite incorporation and mutant analysis studies support the mode-of-action, blockage of DNA synthesis by dual target topoisomerase inhibition. Compound 35 was efficacious in a mouse S. aureus disease model where a 4.5-log reduction in colony forming units versus control was demonstrated.

Reviews citing this publication (1)

  1. Novel compounds targeting bacterial DNA topoisomerase/DNA gyrase. Ehmann DE, Lahiri SD. Curr Opin Pharmacol 18 76-83 (2014)

Articles citing this publication (18)

  1. Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases. Basarab GS, Kern GH, McNulty J, Mueller JP, Lawrence K, Vishwanathan K, Alm RA, Barvian K, Doig P, Galullo V, Gardner H, Gowravaram M, Huband M, Kimzey A, Morningstar M, Kutschke A, Lahiri SD, Perros M, Singh R, Schuck VJ, Tommasi R, Walkup G, Newman JV. Sci Rep 5 11827 (2015)
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  5. NMR structural characterization of the N-terminal active domain of the gyrase B subunit from Pseudomonas aeruginosa and its complex with an inhibitor. Li Y, Wong YX, Poh ZY, Wong YL, Lee MY, Ng HQ, Liu B, Hung AW, Cherian J, Hill J, Keller TH, Kang C. FEBS Lett. 589 2683-2689 (2015)
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  11. Escherichia coli Topoisomerase IV E Subunit and an Inhibitor Binding Mode Revealed by NMR Spectroscopy. Li Y, Wong YL, Ng FM, Liu B, Wong YX, Poh ZY, Liu S, Then SW, Lee MY, Ng HQ, Huang Q, Hung AW, Cherian J, Hill J, Keller TH, Kang C. J. Biol. Chem. 291 17743-17753 (2016)
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  14. Synthesis and Antimicrobial Activity of 4-Chloro-3-Nitrophenylthiourea Derivatives Targeting Bacterial Type II Topoisomerases. Bielenica A, Stępień K, Napiórkowska A, Augustynowicz-Kopeć E, Krukowski S, Włodarczyk M, Struga M. Chem Biol Drug Des 87 905-917 (2016)
  15. Novel diversity-oriented synthesis-derived respiratory syncytial virus inhibitors identified via a high throughput replicon-based screen. Duvall JR, VerPlank L, Ludeke B, McLeod SM, Lee MD, Vishwanathan K, Mulrooney CA, Le Quement S, Yu Q, Palmer MA, Fleming P, Fearns R, Foley MA, Scherer CA. Antiviral Res. 131 19-25 (2016)
  16. Design, synthesis and biological evaluation of 4,5-dibromo-N-(thiazol-2-yl)-1H-pyrrole-2-carboxamide derivatives as novel DNA gyrase inhibitors. Tomašič T, Mirt M, Barančoková M, Ilaš J, Zidar N, Tammela P, Kikelj D. Bioorg. Med. Chem. 25 338-349 (2017)
  17. Pharmacophore generation, atom-based 3D-QSAR and molecular dynamics simulation analyses of pyridine-3-carboxamide-6-yl-urea analogues as potential gyrase B inhibitors. Azam MA, Thathan J. SAR QSAR Environ Res 28 275-296 (2017)
  18. Design, Synthesis, and Evaluation of Novel Tyrosine-Based DNA Gyrase B Inhibitors. Cotman AE, Trampuž M, Brvar M, Kikelj D, Ilaš J, Peterlin-Mašič L, Montalvão S, Tammela P, Frlan R. Arch. Pharm. (Weinheim) 350 (2017)