Lead optimization of 8-(methylamino)-2-oxo-1,2-dihydroquinolines as bacterial type II topoisomerase inhibitors

Autor: Mayumi Endo, Hideaki Amada, Masafumi Kamitani, Takeuchi Tomoki, Norikazu Ohtake, Yunoshin Tamura, Aiko Masuko, Nozomi Tanaka-Yamamoto, Hiroyuki Sugiyama, Fumihito Ushiyama, Yasuhiro Mihara, Kosuke Hitaka, Iichiro Takata, Reiko Wada, Masashi Mima
Rok vydání: 2020
Předmět:
Methicillin-Resistant Staphylococcus aureus
Models
Molecular
Topoisomerase IV
Cell Survival
Clinical Biochemistry
Pharmaceutical Science
Microbial Sensitivity Tests
medicine.disease_cause
01 natural sciences
Biochemistry
DNA gyrase
Microbiology
Vancomycin-Resistant Enterococci
chemistry.chemical_compound
Structure-Activity Relationship
Antibiotic resistance
Transcriptional Regulator ERG
Drug Discovery
Streptococcus pneumoniae
Drug Resistance
Bacterial
medicine
Humans
Topoisomerase II Inhibitors
Molecular Biology
Antibacterial agent
biology
Dose-Response Relationship
Drug
Molecular Structure
010405 organic chemistry
Organic Chemistry
Hep G2 Cells
biochemical phenomena
metabolism
and nutrition
0104 chemical sciences
Anti-Bacterial Agents
010404 medicinal & biomolecular chemistry
DNA Topoisomerases
Type II
chemistry
Staphylococcus aureus
biology.protein
Quinolines
Molecular Medicine
Type II topoisomerase
Lead compound
Zdroj: Bioorganicmedicinal chemistry. 28(22)
ISSN: 1464-3391
Popis: 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 MIC90 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.
Databáze: OpenAIRE
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