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

  • Bioorg Med Chem. 2020 Nov 15;28(22):115776. doi: 10.1016/j.bmc.2020.115776.
Fumihito Ushiyama  1 ,  Hideaki Amada  2 ,  Yasuhiro Mihara  2 ,  Tomoki Takeuchi  2 ,  Nozomi Tanaka-Yamamoto  2 ,  Masashi Mima  2 ,  Masafumi Kamitani  2 ,  Reiko Wada  2 ,  Yunoshin Tamura  2 ,  Mayumi Endo  2 ,  Aiko Masuko  2 ,  Iichiro Takata  2 ,  Kosuke Hitaka  2 ,  Hiroyuki Sugiyama  2 ,  Norikazu Ohtake  2
Affiliations
  • 1. Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-Cho, Kita-Ku, Saitama 331-9530, Japan. Electronic address: [email protected].
  • 2. Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-Cho, Kita-Ku, Saitama 331-9530, Japan.
PMID: 33032189 DOI: 10.1016/j.bmc.2020.115776
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 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.

Keywords
Antibacterial agent; Antimicrobial resistance; Bacterial type II topoisomerase; DNA gyrase; Topoisomerase IV.
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