Synthesis and evaluation of 1-cyclopropyl-2-thioalkyl-8-methoxy fluoroquinolones

Kevin R. Marks; Muhammad Malik; Arkady Mustaev; Hiroshi Hiasa; Karl Drlica; Robert J. Kerns

doi:10.1016/j.bmcl.2011.05.112

Synthesis and evaluation of 1-cyclopropyl-2-thioalkyl-8-methoxy fluoroquinolones

Kevin R. Marks, Muhammad Malik, Arkady Mustaev, Hiroshi Hiasa, Karl Drlica, Robert J. Kerns

Pharmacology

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Novel fluoroquinolone derivatives substituted with a 2-thioalkyl moiety, with and without a concomitant 3-carboxylate group, were synthesized to evaluate the effect of C-2 thioalkyl substituents on gyrase binding and inhibition. The presence of a 2-thioalkyl group universally decreased activity as compared to parent fluoroquinolones. However, with derivatives of moxifloxacin the presence of either a 2-thioalkyl group or a 3-carboxylate moiety increased activity over the 2,3-unsubstituted derivative. Energy minimization of structures provides an explanation for relative activities of fluoroquinolones having a C-2 thio moiety.

Original language	English (US)
Pages (from-to)	4585-4588
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	15
DOIs	https://doi.org/10.1016/j.bmcl.2011.05.112
State	Published - Aug 1 2011

Bibliographical note

Funding Information:
This work was supported by NIH Grants R01-AI73491 and R01-AI087671 .

Keywords

Antibacterial
DNA gyrase
Fluoroquinolone
Moxifloxacin
Ulifloxacin

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10.1016/j.bmcl.2011.05.112

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title = "Synthesis and evaluation of 1-cyclopropyl-2-thioalkyl-8-methoxy fluoroquinolones",

abstract = "Novel fluoroquinolone derivatives substituted with a 2-thioalkyl moiety, with and without a concomitant 3-carboxylate group, were synthesized to evaluate the effect of C-2 thioalkyl substituents on gyrase binding and inhibition. The presence of a 2-thioalkyl group universally decreased activity as compared to parent fluoroquinolones. However, with derivatives of moxifloxacin the presence of either a 2-thioalkyl group or a 3-carboxylate moiety increased activity over the 2,3-unsubstituted derivative. Energy minimization of structures provides an explanation for relative activities of fluoroquinolones having a C-2 thio moiety.",

keywords = "Antibacterial, DNA gyrase, Fluoroquinolone, Moxifloxacin, Ulifloxacin",

author = "Marks, {Kevin R.} and Muhammad Malik and Arkady Mustaev and Hiroshi Hiasa and Karl Drlica and Kerns, {Robert J.}",

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AU - Marks, Kevin R.

AU - Malik, Muhammad

AU - Mustaev, Arkady

AU - Hiasa, Hiroshi

AU - Drlica, Karl

AU - Kerns, Robert J.

N1 - Funding Information: This work was supported by NIH Grants R01-AI73491 and R01-AI087671 .

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N2 - Novel fluoroquinolone derivatives substituted with a 2-thioalkyl moiety, with and without a concomitant 3-carboxylate group, were synthesized to evaluate the effect of C-2 thioalkyl substituents on gyrase binding and inhibition. The presence of a 2-thioalkyl group universally decreased activity as compared to parent fluoroquinolones. However, with derivatives of moxifloxacin the presence of either a 2-thioalkyl group or a 3-carboxylate moiety increased activity over the 2,3-unsubstituted derivative. Energy minimization of structures provides an explanation for relative activities of fluoroquinolones having a C-2 thio moiety.

AB - Novel fluoroquinolone derivatives substituted with a 2-thioalkyl moiety, with and without a concomitant 3-carboxylate group, were synthesized to evaluate the effect of C-2 thioalkyl substituents on gyrase binding and inhibition. The presence of a 2-thioalkyl group universally decreased activity as compared to parent fluoroquinolones. However, with derivatives of moxifloxacin the presence of either a 2-thioalkyl group or a 3-carboxylate moiety increased activity over the 2,3-unsubstituted derivative. Energy minimization of structures provides an explanation for relative activities of fluoroquinolones having a C-2 thio moiety.

KW - Antibacterial

KW - DNA gyrase

KW - Fluoroquinolone

KW - Moxifloxacin

KW - Ulifloxacin

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Synthesis and evaluation of 1-cyclopropyl-2-thioalkyl-8-methoxy fluoroquinolones

Abstract

Bibliographical note

Keywords

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