2018
DOI: 10.1021/acs.jmedchem.8b00114
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Discovery and Optimization of Indolyl-Containing 4-Hydroxy-2-Pyridone Type II DNA Topoisomerase Inhibitors Active against Multidrug Resistant Gram-negative Bacteria

Abstract: There exists an urgent medical need to identify new chemical entities (NCEs) targeting multidrug resistant (MDR) bacterial infections, particularly those caused by Gram-negative pathogens. 4-Hydroxy-2-pyridones represent a novel class of nonfluoroquinolone inhibitors of bacterial type II topoisomerases active against MDR Gram-negative bacteria. Herein, we report on the discovery and structure–activity relationships of a series of fused indolyl-containing 4-hydroxy-2-pyridones with improved in vitro antibacteri… Show more

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Cited by 11 publications
(12 citation statements)
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“…The indole–2‐pyridone hybrids 80a,b (MIC: 0.78–6.3 μg/ml) possessed an excellent broad‐spectrum activity against a panel of wild‐type and drug‐resistant Gram‐negative strains, including permeable E. coli BAS849 ( E. coli p ), wild‐type E. coli ATCC 25922 ( E. coli WT ), highly fluoroquinolone‐resistant E. coli strains SKM18 ( E. coli R1 ) bearing four mutations (two in gyrA and two in parC ) in the quinolone resistance‐determining region (QRDR), and clinical isolate ELZ4251 ( E. coli R2 ), wide‐type strains of A. baumannii ATCC BAA‐747 ( A. bau WT ) and K. pneumoniae ATCC 35657 ( K. pneu WT ), as well as fluoroquinolone‐resistant clinical isolate A. baumannii MMX2240 ( A. bau R ), whereas the reference ciprofloxacin (MIC: >250 μg/ml) was devoid of activity against E. coli R1 , E. coli R2 , and A. bau R . [ 158,159 ] In a murine septicemia model, hybrids 80a,b (20 mg/kg, intravenous administration) showed obvious inhibition in mice infected with a lethal dose of E. coli . The mechanistic study revealed that these two hybrids could target both bacterial DNA gyrase and topoisomerase IV, and they could serve as dual‐action antibacterial candidates.…”
Section: Indole–pyridine/pyrimidine Hybridsmentioning
confidence: 99%
“…The indole–2‐pyridone hybrids 80a,b (MIC: 0.78–6.3 μg/ml) possessed an excellent broad‐spectrum activity against a panel of wild‐type and drug‐resistant Gram‐negative strains, including permeable E. coli BAS849 ( E. coli p ), wild‐type E. coli ATCC 25922 ( E. coli WT ), highly fluoroquinolone‐resistant E. coli strains SKM18 ( E. coli R1 ) bearing four mutations (two in gyrA and two in parC ) in the quinolone resistance‐determining region (QRDR), and clinical isolate ELZ4251 ( E. coli R2 ), wide‐type strains of A. baumannii ATCC BAA‐747 ( A. bau WT ) and K. pneumoniae ATCC 35657 ( K. pneu WT ), as well as fluoroquinolone‐resistant clinical isolate A. baumannii MMX2240 ( A. bau R ), whereas the reference ciprofloxacin (MIC: >250 μg/ml) was devoid of activity against E. coli R1 , E. coli R2 , and A. bau R . [ 158,159 ] In a murine septicemia model, hybrids 80a,b (20 mg/kg, intravenous administration) showed obvious inhibition in mice infected with a lethal dose of E. coli . The mechanistic study revealed that these two hybrids could target both bacterial DNA gyrase and topoisomerase IV, and they could serve as dual‐action antibacterial candidates.…”
Section: Indole–pyridine/pyrimidine Hybridsmentioning
confidence: 99%
“…Increasing resistance to current therapeutics against many pathogenic bacteria 5 (Walsh 2015, Gerasyuto 2018 require new treatment options with unique 6 mechanism(s) of action. Recently, we reported the discovery of a series of fused 7…”
Section: Introductionmentioning
confidence: 99%
“…indolyl-containing 4-hydroxy-2-pyridones that showed inhibited bacterial DNA 8 synthesis by targeting mutant DNA topoisomerases (gyrase, topoisomerase IV) and 9 improved in vitro antibacterial activity against a range of fluoroquinolone resistant Gram negative strains (Gerasyuto 2018).…”
Section: Introductionmentioning
confidence: 99%
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