Synthesis, antibacterial activity and docking of 14-membered 9-O-(3-arylalkyl) oxime 11,12-cyclic carbonate ketolides

Jian Hua Liang; Kun An; Wei Lv; Mark Cushman; He Wang; Ying Chun Xu

doi:10.1016/j.ejmech.2012.10.054

Synthesis, antibacterial activity and docking of 14-membered 9-O-(3-arylalkyl) oxime 11,12-cyclic carbonate ketolides

Jian Hua Liang^*, Kun An, Wei Lv, Mark Cushman, He Wang, Ying Chun Xu

^*Corresponding author for this work

School of Chemistry and Chemical Engineering

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

15 Citations (Scopus)

Abstract

A series of 9-O-(3-aryl-2-propargyl)oxime ketolides 8 was synthesized and evaluated for in vitro antibacterial activity. Among 8, 8b-8d, and 8h-8l displayed dramatically improved potency against inducibly MLS _B-resistant and efflux-resistant pathogens as compared to clarithromycin and azithromycin. Especially, 8i (Ar4-isoquinolyl) possessed an MIC of 0.064 μg/mL against constitutively MLS_B-resistant Streptococcus pneumoniae, and MICs of 0.032-0.064 μg/mL against methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus hominis. The analog 10 with a propyl linker was less effective than both the corresponding 8 and 9 containing propynyl and propenyl linkers. A docking study was performed to gain insight into the binding mode of series 8 and 9 and to rationalize the disparity found in the SAR of 8 and 9.

Original language	English
Pages (from-to)	54-63
Number of pages	10
Journal	European Journal of Medicinal Chemistry
Volume	59
DOIs	https://doi.org/10.1016/j.ejmech.2012.10.054
Publication status	Published - Jan 2013

Keywords

Antibacterial activity
Erythromycin
Ketolide
Macrolide
Multi-drug resistance
Oxime

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10.1016/j.ejmech.2012.10.054

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title = "Synthesis, antibacterial activity and docking of 14-membered 9-O-(3-arylalkyl) oxime 11,12-cyclic carbonate ketolides",

abstract = "A series of 9-O-(3-aryl-2-propargyl)oxime ketolides 8 was synthesized and evaluated for in vitro antibacterial activity. Among 8, 8b-8d, and 8h-8l displayed dramatically improved potency against inducibly MLS B-resistant and efflux-resistant pathogens as compared to clarithromycin and azithromycin. Especially, 8i (Ar4-isoquinolyl) possessed an MIC of 0.064 μg/mL against constitutively MLSB-resistant Streptococcus pneumoniae, and MICs of 0.032-0.064 μg/mL against methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus hominis. The analog 10 with a propyl linker was less effective than both the corresponding 8 and 9 containing propynyl and propenyl linkers. A docking study was performed to gain insight into the binding mode of series 8 and 9 and to rationalize the disparity found in the SAR of 8 and 9.",

keywords = "Antibacterial activity, Erythromycin, Ketolide, Macrolide, Multi-drug resistance, Oxime",

author = "Liang, \{Jian Hua\} and Kun An and Wei Lv and Mark Cushman and He Wang and Xu, \{Ying Chun\}",

year = "2013",

month = jan,

doi = "10.1016/j.ejmech.2012.10.054",

language = "English",

volume = "59",

pages = "54--63",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

publisher = "Elsevier Masson s.r.l.",

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TY - JOUR

T1 - Synthesis, antibacterial activity and docking of 14-membered 9-O-(3-arylalkyl) oxime 11,12-cyclic carbonate ketolides

AU - Liang, Jian Hua

AU - An, Kun

AU - Lv, Wei

AU - Cushman, Mark

AU - Wang, He

AU - Xu, Ying Chun

PY - 2013/1

Y1 - 2013/1

N2 - A series of 9-O-(3-aryl-2-propargyl)oxime ketolides 8 was synthesized and evaluated for in vitro antibacterial activity. Among 8, 8b-8d, and 8h-8l displayed dramatically improved potency against inducibly MLS B-resistant and efflux-resistant pathogens as compared to clarithromycin and azithromycin. Especially, 8i (Ar4-isoquinolyl) possessed an MIC of 0.064 μg/mL against constitutively MLSB-resistant Streptococcus pneumoniae, and MICs of 0.032-0.064 μg/mL against methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus hominis. The analog 10 with a propyl linker was less effective than both the corresponding 8 and 9 containing propynyl and propenyl linkers. A docking study was performed to gain insight into the binding mode of series 8 and 9 and to rationalize the disparity found in the SAR of 8 and 9.

AB - A series of 9-O-(3-aryl-2-propargyl)oxime ketolides 8 was synthesized and evaluated for in vitro antibacterial activity. Among 8, 8b-8d, and 8h-8l displayed dramatically improved potency against inducibly MLS B-resistant and efflux-resistant pathogens as compared to clarithromycin and azithromycin. Especially, 8i (Ar4-isoquinolyl) possessed an MIC of 0.064 μg/mL against constitutively MLSB-resistant Streptococcus pneumoniae, and MICs of 0.032-0.064 μg/mL against methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus hominis. The analog 10 with a propyl linker was less effective than both the corresponding 8 and 9 containing propynyl and propenyl linkers. A docking study was performed to gain insight into the binding mode of series 8 and 9 and to rationalize the disparity found in the SAR of 8 and 9.

KW - Antibacterial activity

KW - Erythromycin

KW - Ketolide

KW - Macrolide

KW - Multi-drug resistance

KW - Oxime

UR - https://www.scopus.com/pages/publications/84870217771

U2 - 10.1016/j.ejmech.2012.10.054

DO - 10.1016/j.ejmech.2012.10.054

M3 - Article

C2 - 23202851

AN - SCOPUS:84870217771

SN - 0223-5234

VL - 59

SP - 54

EP - 63

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

Synthesis, antibacterial activity and docking of 14-membered 9-O-(3-arylalkyl) oxime 11,12-cyclic carbonate ketolides

Abstract

Keywords

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