5-(2-Pyrimidinyl)-imidazo[1,2-a]pyridines are antibacterial agents targeting the ATPase domains of DNA gyrase and topoisomerase IV

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 18, 2009, Pages 5302-5306

  Starr, Jeremy T ^a   Sciotti, Richard J ^a   Hanna, Debra L ^a   Huband, Michael D ^a   Mullins, Lisa M ^a   Cai, Hongliang ^a   Gage, Jeffrey W ^a   Lockard, Mandy ^a   Rauckhorst, Mark R ^a   Owen, Robert M ^a   Lall, Manjinder S ^a   Tomilo, Mark ^a   Chen, Huifen ^a   McCurdy, Sandra P ^a   Barbachyn, Michael R ^a  

^a PFIZER INC   (United States)

Author keywords

Antibacterial; Gram positive; Gyrase; GyrB

Indexed keywords

5 (2 PYRIMIDINYL)IMIDAZO[1,2 A]PYRIDINE DERIVATIVE; ADENOSINE TRIPHOSPHATASE; ANTIINFECTIVE AGENT; DNA TOPOISOMERASE (ATP HYDROLYSING); DNA TOPOISOMERASE IV; GYRASE INHIBITOR; NOVOBIOCIN; PYRIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BACTERIAL GENE; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; GYRB GENE; LUNG INFECTION; METHICILLIN RESISTANT STAPHYLOCOCCUS AUREUS; MINIMUM INHIBITORY CONCENTRATION; MOUSE; NONHUMAN; PARE GENE; SEPSIS;

ANIMALS; ANTI-BACTERIAL AGENTS; DNA GYRASE; DNA TOPOISOMERASE IV; GRAM-POSITIVE BACTERIA; IMIDAZOLES; LUNG; MICE; MICROBIAL SENSITIVITY TESTS; PYRIDINES; PYRIMIDINES; RATS; SEPSIS; STRUCTURE-ACTIVITY RELATIONSHIP;

BACTERIA (MICROORGANISMS); POSIBACTERIA;

EID: 68949174105     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.07.141     Document Type: Article

References (32)

1. Aspa J., Rajas O., and Rodriguez de Castro F. Expert Opin. Pharmacother. 9 (2008) 229
2. Van Bambeke F., Reinert R.R., Appelbaum P.C., Tulkens P.M., and Peetermans W.E. Drugs 67 (2007) 2355
3. Co-crystal structures of clinafloxacin and moxifloxacin bound with DNA and Streptococcus pneumoniae topoisomerase IV were recently reported:. Laponogov I., Sohi M.K., Veselkov D.A., Pan X.-S., Sawhney R., Thompson A.W., McAuley K.E., Fisher L.M., and Sanderson M.R. Nat. Struct. Mol. Biol. 16 (2009) 667
4. For a recent discussion of the FQ mechanism see:. Drlica K., Malik M., Kerns R.J., and Zhao X. Antimicrob. Agents Chemother. 52 (2008) 385
5. For the novobiocin mechanism see:. Ali J.A., Jackson A.P., Howells A.J., and Maxwell A. Biochemistry 32 (1993) 2717
6. Maxwell A. Mol. Microbiol. 9 (1993) 681
7. Kampranis S.C., Gormley N.A., Tranter R., Orphanides G., and Maxwell A. Biochemistry 38 (1999) 1967
8. Tsai F.T.F., Singh O.M.P., Skarzynski T., Wonacott A.J., Weston S., Tucker A., Pauptit R.A., Breeze A.L., Poyser J.P., O'Brien R., Ladbury J.E., and Wigley D.B. Proteins: Struct., Funct., Bioinf. 28 (1997) 41
9. Brino L., Urzhumstev A., Mousli M., Bronner C., Mitschler A., Oudet P., and Moras D. J. Biol. Chem. 275 (2000) 9468
10. Dale G.E., Kostrewa D., Gsell B., Stieger M., and D'Arcy A. Acta Crystallogr., Sect. D 55 (1999) 1626
11. Lewis R.J., Singh O.M.P., Smith C.V., Skarzynski T., Maxwell A., Wonacott A.J., and Wigley D.B. EMBO J. 15 (1996) 1412
12. Bellon S., Parsons J.D., Wei Y., Hayakawa K., Swenson L.L., Charifson P.S., Lippke J.A., Aldape R., and Gross C.H. Antimicrob. Agents Chemother. 48 (2004) 1856
13. Charifson P.S., Grillot A.-L., Grossman T.H., Parsons J.D., Badia M., Bellon S., Deininger D.D., Drumm J.E., Gross C.H., LeTiran A., Liao Y., Mani N., Nicolau D.P., Perola E., Ronkin S., Shannon D., Swenson L.L., Tang Q., Tessier P.R., Tian S.-K., Trudeau M., Wang T., Wei Y., Zhang H., and Stamos D. J. Med. Chem. 51 (2008) 5243
14. Grossman T.H., Bartels D.J., Mullin S., Gross C.H., Parsons J.D., Liao Y., Grillot A.-L., Stamos D., Olson E.R., Charifson P.S., and Mani N. Antimicrob. Agents Chemother. 51 (2007) 657
15. Mani N., Gross C.H., Parsons J.D., Hanzelka B., Muh U., Mullin S., Liao Y., Grillot A.-L., Stamos D., Charifson P.S., and Grossman T.H. Antimicrob. Agents Chemother. 50 (2006) 1228
16. Tanitame A., Oyamada Y., Ofuji K., Terauchi H., Kawasaki M., Wachi M., and Yamagishi J.-i. Bioorg. Med. Chem. Lett. 15 (2005) 4299
17. Tanitame A., Oyamada Y., Ofuji K., Fujimoto M., Suzuki K., Ueda T., Terauchi H., Kawasaki M., Nagai K., Wachi M., and Yamagishi J.-i. Bioorg. Med. Chem. 12 (2004) 5515
18. Tanitame A., Oyamada Y., Ofuji K., Fujimoto M., Iwai N., Hiyama Y., Suzuki K., Ito H., Terauchi H., Kawasaki M., Nagai K., Wachi M., and Yamagishi J.-I. J. Med. Chem. 47 (2004) 3693
19. Tanitame A., Oyamada Y., Ofuji K., Suzuki K., Ito H., Kawasaki M., Wachi M., and Yamagishi J.-i. Bioorg. Med. Chem. Lett. 14 (2004) 2863
20. Tanitame A., Oyamada Y., Ofuji K., Kyoya Y., Suzuki K., Ito H., Kawasaki M., Nagai K., Wachi M., and Yamagishi J.n.-i. Bioorg. Med. Chem. Lett. 14 (2004) 2857
21. East S.P., White C.B., Barker O., Barker S., Bennett J., Brown D., Boyd E.A., Brennan C., Chowdhury C., Collins I., Convers-Reignier E., Dymock B.W., Fletcher R., Haydon D.J., Gardiner M., Hatcher S., Ingram P., Lancett P., Mortenson P., Papadopoulos K., Smee C., Thomaides-Brears H.B., Tye H., Workman J., and Czaplewski L.G. Bioorg. Med. Chem. Lett. 19 (2009) 894
22. Yager, K.; Chu, S.; Appelt, K.; Li, X. US patent appl. US 20050054697, 2005.
23. Haydon, D. R.; Czaplewski, L. G.; Palmer, N. J.; Mitchell, D. R.; Atherall, J. F.; Steele, C. R.; Ladduwahetty, T. Int. Pat. Appl. WO 2007148093, 2007.
24. (a) Dumas, J.; Sherer, B. Int. Pat. Appl. WO 2009027733, 2009; (b) Basarab, G.; Hill, P.; Zhou, F. Int. Pat. Appl. WO 2008152418, 2008.
25. Oblak M., Kotnik M., and Solmajer T. Curr. Med. Chem. 14 (2007) 2033 and references therein
26. Butler, D. C. D.; Chen, H.; Hegde, V. R.; Limberakis, C.; Rasne, R. M.; Sciotti, R. J.; Starr, J. T. Int. Pat. Appl. WO 2006038116, 2006.
27. Sciotti, R. J.; Starr, J. T.; Richardson, C.; Rewcastle, G. W.; Palmer, B. D.; Sutherland, H. S.; Spicer, J. A.; Chen, H. Int. Pat. Appl. WO 2005089763, 2005.
28. For example, the synthesis of compound 32 is described in Ref. 13.
29. 2 and the reaction was heated to reflux for 3 h. The reaction was then cooled to 23 °C and evaporated in vacuo to give a brown residue that was partitioned between 1 M HCl and dichloromethane. The aqueous layer was collected and the organic layer was extracted 2 × 1 M HCl then the combined aqueous layers were washed 1 × dichloromethane. The combined aqueous layers were then neutralized with sodium bicarbonate and extracted 3 × dichloromethane. The combined organic extracts were dried over sodium sulfate, evaporated in vacuo, and purified by silica gel chromatography (2-10% isopropanol/dichloromethane) to give 0.540 g (66.3%) of 7-(pyridin-3-yl)-5-(pyrimidin-2-yl)imidazo[1,2-a]pyridine. (g) To a preformed solution of ethylurea (1.74 g, 19.7 mmol) and bromine (1.26 g, 7.90 mmol) in 20 mL dichloromethane was added 7-(pyridin-3-yl)-5-(pyrimidin-2-yl)imidazo[1,2-a]pyridine (0.540 g, 1.97 mmol) and the resulting red solution was stirred at rt for 1 h. It was then poured into ice-cold aqueous sodium hydrogen sulfite (200 mL × 0.050 g/ml) and the bright yellow reaction was neutralized with sodium bicarbonate and extracted 3 × 10% isopropanol/dichloromethane. The combined organic extracts were dried over sodium sulfate and evaporated then purified by silica gel chromatography (5-30-60% isopropanol/dichloromethane).
30. Clinical and Laboratory Standards Institute Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard, 6th ed.; NCCLS Document M11-A6; Vol. 24, No. 2.
31. For gyrB see:. Miller J.R., Herberg J.T., Tomilo M., McCroskey M.C., and Feilmeier B.J. Anal. Biochem. 365 (2007) 132
32. 2, 0.02% (v/v) Tween 20, 0.018% polyethyleneimine, 0.03% butylperflorosulfonate, and 66 μg/mL Streptococcus pneumoniae ParE. The reaction was initiated by addition of 10 μL of a solution containing 3 mM ATP and 0.02% Tween 20 and allowed to proceed for 30 min. The ATPase activity was quenched and orthophosphate detected by addition of 30 μL of a solution consisting of equal volumes of 4.2% (w/v) ammonium molybdate in 4 M HCl and 0.135% (w/v) malachite green in 20% (w/v) glycerol. The plate was briefly shaken and the absorbance at 650 nm was determined using a Spectramax plate reader (Molecular Devices).