4lp0 Citations

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


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 (20)

  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)
  2. A novel inhibitor of gyrase B is a potent drug candidate for treatment of tuberculosis and nontuberculosis mycobacterial infections. Locher CP, Jones SM, Hanzelka BL, Perola E, Shoen CM, Cynamon MH, Ngwane AH, Wiid IJ, van Helden PD, Betoudji F, Nuermberger EL, Thomson JA. Antimicrob Agents Chemother 59 1455-1465 (2015)
  3. Synthesis, structure-activity relationship studies, and antibacterial evaluation of 4-chromanones and chalcones, as well as olympicin A and derivatives. Feng L, Maddox MM, Alam MZ, Tsutsumi LS, Narula G, Bruhn DF, Wu X, Sandhaus S, Lee RB, Simmons CJ, Tse-Dinh YC, Hurdle JG, Lee RE, Sun D. J Med Chem 57 8398-8420 (2014)
  4. Inactivation of multiple bacterial histidine kinases by targeting the ATP-binding domain. Wilke KE, Francis S, Carlson EE. ACS Chem Biol 10 328-335 (2015)
  5. Structure-guided design and development of novel benzimidazole class of compounds targeting DNA gyraseB enzyme of Staphylococcus aureus. Janupally R, Jeankumar VU, Bobesh KA, Soni V, Devi PB, Pulla VK, Suryadevara P, Chennubhotla KS, Kulkarni P, Yogeeswari P, Sriram D. Bioorg Med Chem 22 5970-5987 (2014)
  6. 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)
  7. A novel high-throughput cell-based assay aimed at identifying inhibitors of DNA metabolism in bacteria. Fan J, de Jonge BL, MacCormack K, Sriram S, McLaughlin RE, Plant H, Preston M, Fleming PR, Albert R, Foulk M, Mills SD. Antimicrob Agents Chemother 58 7264-7272 (2014)
  8. Fragment-based discovery of DNA gyrase inhibitors targeting the ATPase subunit of GyrB. Mesleh MF, Cross JB, Zhang J, Kahmann J, Andersen OA, Barker J, Cheng RK, Felicetti B, Wood M, Hadfield AT, Scheich C, Moy TI, Yang Q, Shotwell J, Nguyen K, Lippa B, Dolle R, Ryan MD. Bioorg Med Chem Lett 26 1314-1318 (2016)
  9. Supramolecular pyridyl urea gels as soft matter with antibacterial properties against MRSA and/or E. coli. Pandurangan K, Kitchen JA, Blasco S, Paradisi F, Gunnlaugsson T. Chem Commun (Camb) 50 10819-10822 (2014)
  10. 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)
  11. 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)
  12. Biophysical Studies of Bacterial Topoisomerases Substantiate Their Binding Modes to an Inhibitor. Kang C, Li Y, Cherian J, Liu B, Ng HQ, Lee MY, Binte Ahmad NH, Poh ZY, Wong YX, Huang Q, Wong YL, Hung AW, Hill J, Keller TH. Biophys J 109 1969-1977 (2015)
  13. Repurposing the antihistamine terfenadine for antimicrobial activity against Staphylococcus aureus. Perlmutter JI, Forbes LT, Krysan DJ, Ebsworth-Mojica K, Colquhoun JM, Wang JL, Dunman PM, Flaherty DP. J Med Chem 57 8540-8562 (2014)
  14. Backbone assignment of the N-terminal 24-kDa fragment of Escherichia coli topoisomerase IV ParE subunit. Li Y, Wong YL, Lee MY, Ng HQ, Kang C. Biomol NMR Assign 10 135-138 (2016)
  15. 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)
  16. 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)
  17. 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)
  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)
  19. Synthesis and Evaluation of N-Phenylpyrrolamides as DNA Gyrase B Inhibitors. Durcik M, Tammela P, Barančoková M, Tomašič T, Ilaš J, Kikelj D, Zidar N. ChemMedChem 13 186-198 (2018)
  20. Design, synthesis, and biological evaluation of 1-ethyl-3-(thiazol-2-yl)urea derivatives as Escherichia coli DNA gyrase inhibitors. Tomašič T, Barančoková M, Zidar N, Ilaš J, Tammela P, Kikelj D. Arch Pharm (Weinheim) 351 (2018)