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


Bioorganic & Medicinal Chemistry


Fumihito Ushiyama, Hideaki Amada, Yasuhiro Mihara, Tomoki Takeuchi, Nozomi Tanaka-Yamamoto Masashi Mima, Masafumi Kamitani, Reiko Wada, Yunoshin Tamura, Mayumi Endo, Aiko Masuko, Iichiro Takata, Kosuke Hitaka, Hiroyuki, Sugiyama, Norikazu Ohtake



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 (GPRS) 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.

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