Hybrid antibacterials. DNA polymerase-topoisomerase inhibitors

Journal of Medicinal Chemistry

Volumn 49, Issue 4, 2006, Pages 1455-1465

  Zhi, Chengxin ^a   Long, Zheng Yu ^a   Manikowski, Andrzej ^a   Comstock, Jeanne ^a   Xu, Wei Chu ^a   Brown, Neal C ^a   Tarantino Jr , Paul M ^a   Holm, Karsten A ^a   Dix, Edward J ^a   Wright, George E ^a   Barnes, Marjorie H ^b   Butler, Michelle M ^b   Foster, Kimberly A ^b   LaMarr, William A ^b   Bachand, Benoit ^c   Bethell, Richard ^c,d   Cadilhac, Caroline ^c   Charron, Sylvie ^c   Lamothe, Serge ^c   Motorina, Irina ^c   Storer, Richard ^c,e   more..

^a GLSYNTHESIS INC   (United States)

^b MICROBIOTIX INC   (United States)

^c Shire Canada   (Canada)

^d BOEHRINGER INGELHEIM CANADA LTD   (Canada)

^e Laboratoires Idenix   (France)

Author keywords

[No Author keywords available]

Indexed keywords

3 [4 [1 (1 CYCLOPROPYL 3 CARBOXY 4 OXO 6 FLUORO 7 QUINOLYL) 4 (3 METHYLPIPERAZINYL)]BUTYL] 6 (3 ETHYL 4 METHYLANILINO)URACIL; 3 [4 [1 (1 CYCLOPROPYL 3 CARBOXY 4 OXO 6 FLUORO 7 QUINOLYL) 4 PIPERAZINYL]BUTYL] 6 (3 ETHYL 4 METHYLANILINO)URACIL; 3 [4 [1 (1 CYCLOPROPYL 3 CARBOXY 4 OXO 6 FLUORO 8 METHOXY 7 QUINOLYL) 4 PIPERAZINYL]BUTYL] 6 (3 ETHYL 4 METHYLANILINO)URACIL; 3 [4 [1 (1 CYCLOPROPYL 3 CARBOXY 4 OXO 6,8 DIFLUORO 7 QUINOLYL) 4 (3 HYDROXYMETHYLPIPERAZINYL)]BUTYL] 6 (3 ETHYL 4 METHYLANILINO)URACIL; 3 [4 [1 (1 CYCLOPROPYL 3 CARBOXY 4 OXO 6,8 DIFLUORO 7 QUINOLYL) 4 (3 METHYLPIPERAZINYL)]BUTYL] 6 (3 ETHYL 4 METHYLANILINO)URACIL; 3 [4 [1 [1 (2,4 DIFLUOROPHENYL) 3 CARBOXY 4 OXO 6 FLUORO 7 QUINOLYL] 4 PIPERAZINYL]BUTYL] 6 (3 ETHYL 4 METHYLANILINO)URACIL; ANTIBIOTIC AGENT; CIPROFLOXACIN; DNA POLYMERASE INHIBITOR; DNA TOPOISOMERASE (ATP HYDROLYSING); DNA TOPOISOMERASE INHIBITOR; DNA TOPOISOMERASE IV; GYRASE INHIBITOR; LINEZOLID; NALIDIXIC ACID; NORFLOXACIN; SPARFLOXACIN; TEMAFLOXACIN; UNCLASSIFIED DRUG; VANCOMYCIN;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIBACTERIAL ACTIVITY; ANTIBIOTIC RESISTANCE; ANTIBIOTIC SENSITIVITY; ARTICLE; CONTROLLED STUDY; DOSE RESPONSE; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TARGETING; ENZYME INHIBITION; GRAM POSITIVE BACTERIUM; LETHALITY; MALE; MOUSE; NONHUMAN; STAPHYLOCOCCUS AUREUS; STAPHYLOCOCCUS INFECTION; STRUCTURE ACTIVITY RELATION;

ACUTE TOXICITY TESTS; ANILINE COMPOUNDS; ANIMALS; ANTI-BACTERIAL AGENTS; DNA GYRASE; DNA POLYMERASE III; DRUG RESISTANCE, BACTERIAL; GRAM-POSITIVE BACTERIA; MALE; MICE; STAPHYLOCOCCAL INFECTIONS; STAPHYLOCOCCUS AUREUS; STRUCTURE-ACTIVITY RELATIONSHIP; URACIL;

EID: 33144490048     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0510023     Document Type: Article

References (31)

1. Tarantino, P.; Zhi, C.; Gambino, J.; Wright, G. E.; Brown, N. C. 6-Anilinouracil-based Inhibitors of Bacillus subtilis DNA Polymerase III: Antipolymerase and Antimicrobial Structure-Activity Relationships Based on Substitution at Uracil N3. J. Med. Chem. 1999, 42, 2035-2040.
2. Tarantino, P.; Zhi, C.; Wright, G. E.; Brown, N. C. Inhibitors of DNA Polymerase III as Novel Antimicrobial Agents against Gram-positive Eubacteria. Antimicrob. Agents Chemother. 1999, 43, 1982-1987.
3. Zhi, C.; Long, Z.-Y., Gambino, J.; Xu, W.-C.; Brown, N. C.; Barnes, M.; Butler, M.; LaMarr, W.; Wright G. E. Synthesis of Substituted 6-Aminouracils and Their Inhibition of DNA Polymerase IIIC and Gram-positive Bacterial Growth. J. Med. Chem. 2003, 46, 2731-2739.
4. Zhi, C.; Long, Z.-Y.; Manikowski, A.; Brown, N. C.; Tarantino, P. M., Jr.; Holm, K. A.; Dix, E.; Wright, G. E.; Foster, K. A.; Butler, M. M.; LaMarr, W. A.; Skow, D. J.; Lamothe, S.; Motorina, I. Synthesis and Antibacterial Activity of 3-Substituted-6-(3-ethyl-4-methylanilino)uracils. J. Med. Chem. 2005, 48, 7063-7074.
5. Kuhl, L.; Svenstrup, N.; Ladel, C.; Otteneder, M.; Binas, A.; Schiffer, G.; Brands, M.; Lampe, T.; Ziegelbauer, K.; Rübsamen-Waigmann, H.; Haebich, D.; Ehlert, K. Biological Characterization of Novel Inhibitors of the Gram-Positive DNA Polymerase IIIC Enzyme. Antimicrob. Agents Chemother. 2005, 49, 987-995.
6. Chu, D. T. W.; Fernandes, P. B. Structure-Activity Relationships of the Fluoroquinolones. Antimicrob. Agents Chemother. 1989, 33, 131-135.
7. Andriole, V. T., Ed. The Quinolones, 3rd ed.; Academic Press: London, 2000.
8. Childs, S. J. Safety of the Fluoroquinolone Antibiotics: Focus on Molecular Structure. Infect. Urol. 2000, 13, 3-10.
9. Lipsky, B. A.; Baker, C. A. Fluoroquinolone Toxicity Profiles. A Review Focusing on Newer Agents. Clin. Infect. Dis. 1999, 28, 352-364.
10. Hammond, R.; Barnes, M.; Mack, S.; Mitchener, J.; Brown, N. Bacillus subtilis DNA polymerase III: complete sequence, overexpression, and characterization of the polC gene. Gene 1991, 98, 29-36.
11. Chu, D. T. W.; Nordeen, C. W.; Hardy, D. J.; Swanson, R. N.; Giardina, W. J.; Pernet, A. G.; Plattner, J. J. Synthesis, Antibacterial Activities, and Pharmacological Properties of Enantiomers of Temafloxacin Hydrochloride. J. Med. Chem. 1991, 34, 168-174.
12. Barnes, M. H.; LaMarr, W. A.; Foster, K. A. DNA gyrase and DNA topoisomerase of Bacillus subtilis: expression and characterization of recombinant enzymes encoded by the gyrA, gyrB, parC and parE genes. Protein Expression Purif. 2003, 29, 259-264.
13. Butler, M. M.; LaMarr, W. A.; Foster, K. A.; Barnes, M. H.; Skow, D. J.; Lyden, P. T.; Zhi, C.; Brown, N. C.; Wright, G. E.; Bowlin, T. L. Antibacterial Activity and Mechanism of Action of Novel Anilinouracil:Fluoroquinolone Hybrid Compounds. Antimicrob. Agents Chemother., submitted for publication.
14. Borner, K.; Lode, H. Biotransformation of selected gyrase inhibitors. Infection 1986, 14, S54-S59.
15. Campoli-Richards, D. M.; Monk, J. P.; Price, A.; Benfield, P.; Todd, P. A.; Ward, A. Ciprofloxacin. A Review of its Antibacterial Activity, Pharmacokinetic Properties and Therapeutic Use. Drugs 1988, 35, 373-447.
16. Hamilton-Miller, J. M. T. Dual-action Antibiotic Hybrids. J. Antimicrob. Chemother. 1994, 33, 197-200.
17. Jucker, E.; Rissi, E. Über C-substituierte Piperazinderivate. Helv. Chim. Acta 1962, 45, 2383-2402.
18. Jung, M. E.; Yang, E. C.; Vu, B. T.; Kiankarimi, M.; Spyrou, E.; Kaunitz, J. Glycosylation of Fluoroquinolones through Direct and Oxygenated Polymethylene Linkages as a Sugar-Mediated Active Transport System for Antimicrobials. J. Med. Chem. 1999, 42, 3899-3909.
19. Matsumoto, J.; Takase, Y.; Nishimura, Y. Naphthyridine derivatives, process for their preparation and pharmaceutical compositions containing them. Eur. Pat. Appl. EP0027752A1, 1980.
20. Koga, H.; Itoh, A.; Murayama, S.; Suzue, S.; Irikura, T. Structure-Activity relationships of Antibacterial 6,7- and 7,8-Disubstituted 1-Alkyl-1,4-dihydro-4-oxoquinoline-3-carboxylic Acids. J. Med. Chem. 1980, 25, 1358-1363.
21. Irakura, T.; Suzue, S.; Murayama, S.; Hirai, K.; Ishizaki, T. Quinolinecarboxylic acid derivatives and process for their preparation. Eur. Pat. Appl. EP195841A1, 1986.
22. McGuirk, P. R. 1,4-Dihydro-4-oxo-3-quinoline derivatives as selectively toxic mammalian antibacterial agents. U.S. Patent 5,385,913, 1995.
23. Iwata, M.; Kimura, T.; Inoue, T. 4-Oxoquinoline-3-carboxylic acid derivatives, their preparation and their use. Eur. Pat. Appl. EP0352123B1, 1989.
24. Remuzon, P.; Bouzard, D.; Di Cesare, P.; Jacquet, J. P.; Kiechel, J. R.; Ledoussal, B.; Kessler, R. E.; Fung-Tomc, J. Fluoronaphthyridines and -quinolones as Antibacterial Agents. 3. Synthesis and Structure-Activity Relationships of New 1-(1,1-Dimethyl-2-fluoroethyl), 1-[1-Methyl-1-(fluoroethyl) ], and 1-[1,1-(Difluoromethyl)-2-fluoroethyl] Substituted Derivatives. J. Med. Chem. 1991, 34, 29-37.
25. Chu, D. T. W.; Fernandes, P. B.; Claiborne, A. K.; Pihuleac, E.; Nordeen, C. W.; Malerczka, R. E., Jr.; Pernet, A. G. Synthesis and Structure-Activity Relationships of Novel Arylfluoroquinolone Antibacterial Agents. J. Med. Chem. 1985, 28, 1558-1564.
26. Domagala, J. M.; Heifetz, C. L.; Hutt, M. P.; Mich, T. F.; Nichols, J. B.; Solomon, M.; Worth, D. F. 1-Substituted 7-[3-[(Ethylamino)-methyl]-1- pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic Acids. New Quantitative Structure-Activity Relationships at Ni for the Quinolone Antibacterials. J. Med. Chem. 1988, 31, 991-1001.
27. Irikura, T.; Suzue, S.; Hirai, K.; Ishizaki, T. Quinolinecarboxylic acid derivatives. Eur. Pat. Appl. EP178388A1, 1986.
28. Okada, T.; Ezumi, K.; Yamakawa, M.; Sato, H.; Tsuji, T.; Tsushima, T.; Motokawa, K.; Komatsu, Y. Quantitative Structure-activity Relationships of Antibacterial Agents. 7-Heterocyclic Amine Substituted 1-Cyclopropyl-6,8- difluoro-4-oxoquinolone-3-carboxylic acids. Chem. Pharm. Bull 1993, 41, 126-131.
29. Petersen, U.; Himmler, T.; Schenke, T.; Krebs, K.; Grohe, K.; Bremm, K.-D.; Metzger, K. G.; Endermann, R.; Zeiler, H.-J. 8-Vinyl- and 9-ethinyl-quinolone-carboxylic acids. U.S. Patent 5,468,742, 1995.
30. Barnes, M. H.; Brown, N. C. Antibody to B. subtilis DNA polymerase III: use in enzyme purification and examination of homology among replication-specific DNA polymerases. Nucleic Acids Res. 1979, 6, 1203-1219.
31. Wright, G. E.; Brown, N. C. Inhibition of Bacillus subtilis DNA Polymerase III by Arylhydrazinopyrimidines: Novel Properties of 2-Thiouracil Derivatives. Biochim. Biophys. Acta 1976, 432, 37-48.