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

被引：10

作者：

Ushiyama, Fumihito ^{[1
]}

Amada, Hideaki ^{[1
]}

Mihara, Yasuhiro ^{[1
]}

Takeuchi, Tomoki ^{[1
]}

Tanaka-Yamamoto, Nozomi ^{[1
]}

Mima, Masashi ^{[1
]}

Kamitani, Masafumi ^{[1
]}

Wada, Reiko ^{[1
]}

Tamura, Yunoshin ^{[1
]}

Endo, Mayumi ^{[1
]}

Masuko, Aiko ^{[1
]}

Takata, Iichiro ^{[1
]}

Hitaka, Kosuke ^{[1
]}

Sugiyama, Hiroyuki ^{[1
]}

Ohtake, Norikazu ^{[1
]}

机构：

[1] Taisho Pharmaceut Co Ltd, Kita Ku, 1-403 Yoshino Cho, Saitama 3319530, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2020年 / 28卷 / 22期

关键词：

Bacterial type II topoisomerase; DNA gyrase; Topoisomerase IV; Antimicrobial resistance; Antibacterial agent; MOLECULAR-ORBITAL METHOD; DNA GYRASE; ESCHERICHIA-COLI; DRUG DISCOVERY; IV; RESISTANCE; GYRB; IDENTIFICATION; ENTEROCOCCI; MECHANISMS;

D O I：

10.1016/j.bmc.2020.115776

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 mu g/mL, respectively. Hence, TP0480066 can be regarded as a promising antibacterial drug candidate of this chemical class.

引用

页数：14

共 11 条

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