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Lead optimization of 8-(methylamino)-2-oxo-1,2-dihydroquinolines as bacterial type II topoisomerase inhibitors.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2020 Nov 15; Vol. 28 (22), pp. 115776. Date of Electronic Publication: 2020 Sep 22. - Publication Year :
- 2020
-
Abstract
- The global increase in multidrug-resistant pathogens has caused severe problems in the treatment of infections. To overcome these difficulties, the advent of a new chemical class of antibacterial drug is eagerly desired. We aimed at creating novel antibacterial agents against bacterial type II topoisomerases, which are well-validated targets. TP0480066 (compound 32) has been identified by using structure-based optimization originated from lead compound 1, which was obtained as a result of our previous lead identification studies. The MIC <subscript>90</subscript> values of TP0480066 against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), and genotype penicillin-resistant Streptococcus pneumoniae (gPRSP) were 0.25, 0.015, and 0.06 μg/mL, respectively. Hence, TP0480066 can be regarded as a promising antibacterial drug candidate of this chemical class.<br /> (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Subjects :
- Anti-Bacterial Agents chemical synthesis
Anti-Bacterial Agents chemistry
Cell Survival drug effects
Dose-Response Relationship, Drug
Drug Resistance, Bacterial drug effects
Hep G2 Cells
Humans
Methicillin-Resistant Staphylococcus aureus drug effects
Methicillin-Resistant Staphylococcus aureus enzymology
Microbial Sensitivity Tests
Models, Molecular
Molecular Structure
Quinolines chemical synthesis
Quinolines chemistry
Streptococcus pneumoniae drug effects
Streptococcus pneumoniae enzymology
Structure-Activity Relationship
Topoisomerase II Inhibitors chemical synthesis
Topoisomerase II Inhibitors chemistry
Transcriptional Regulator ERG antagonists & inhibitors
Transcriptional Regulator ERG metabolism
Vancomycin-Resistant Enterococci drug effects
Vancomycin-Resistant Enterococci enzymology
Anti-Bacterial Agents pharmacology
DNA Topoisomerases, Type II metabolism
Quinolines pharmacology
Topoisomerase II Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 28
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33032189
- Full Text :
- https://doi.org/10.1016/j.bmc.2020.115776