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Chapter 1 : Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not

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Abstract:

The review by Domagala in 1994 represented one of the first attempts to simultaneously delineate the structure-activity relationships (SARs) of both activity and side effects providing some insights as to where the future of the quinolones might reside. A significant conclusion of this work was that the side chain at C-7 in conjunction with that at C-8 would be the main focus of successful quinolone manipulation; all other positions were viewed as optimal. The chiral form of the fluorocyclopropyl group slightly affects the overall antibacterial activity, with a two- to four-fold difference in potency between the most active stereoisomer and the least active; overall, the isomer was more efficacious than the isomer. The 2 pyridones, which were introduced in 1994, represent a new structural class of "quinolone-type" antibacterials. The fluoroquinolones derived their name from the dogma that the 6-fluoro group was an essential feature of the broad-spectrum quinolones that first appeared in the late 1970s. Extensive SAR work on 7-(3-amino)-azetidinyl quinolones such as E-4695 (structure 35) has been reported. Initial success with the 3-amino derivatives led to further exploration of 2-alkyl-3-amino analogs (structure 36) with particular emphasis on the effects of stereochemistry on antibacterial activity. The reality of the quinolone SAR efforts is that all the potency ever required was already in hand in the early 1990s.

Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
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Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
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Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
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Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
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Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
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Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
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Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
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Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
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Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
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Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
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Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
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Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
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Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
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Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
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Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
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Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
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Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
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Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
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Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
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Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
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Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
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Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
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Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
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Tables

Generic image for table
Table 1

MICs of structures 11 and 12

Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
Generic image for table
Table 2

MICs and gyrase inhibition of compound 30

Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1
Generic image for table
Table 3

Effect of a fluorine at position 6 on genotoxicity

Citation: Domagala J, Hagen S. 2003. Structure-Activity Relationships of the Quinolone Antibacterials in the New Millennium: Some Things Change and Some Do Not, p 3-18. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch1

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