LpxC Inhibitors: Design, Synthesis, and Biological Evaluation of Oxazolidinones as Gram-negative Antibacterial Agents.
Herein we report a scaffold-hopping approach to identify a new scaffold with a zinc binding headgroup. Structural information was used to give novel oxazolidinone-based LpxC inhibitors. In particular, the most potent compound, 23j, showed a low efflux ratio, nanomolar potencies against E. coli LpxC enzyme, and excellent antibacterial activity against E. coli and K. pneumoniae. Computational docking was used to predict the interaction between 23j and E. coli LpxC, suggesting that the interactions with C207 and C63 contribute to the strong activity. These results provide new insights into the design of next-generation LpxC inhibitors.
Watarase Research Center, Kyorin Pharmaceutical Co., Ltd. , 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Haruaki
H
Kurasaki
Watarase Research Center, Kyorin Pharmaceutical Co., Ltd. , 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Kosuke
K
Tsuda
Watarase Research Center, Kyorin Pharmaceutical Co., Ltd. , 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Mariko
M
Shinoyama
Watarase Research Center, Kyorin Pharmaceutical Co., Ltd. , 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Noriko
N
Takaya
Watarase Research Center, Kyorin Pharmaceutical Co., Ltd. , 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Yuko
Y
Yamaguchi
Watarase Research Center, Kyorin Pharmaceutical Co., Ltd. , 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Ryuta
R
Kishii
Watarase Research Center, Kyorin Pharmaceutical Co., Ltd. , 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Kazuhiko
K
Iwase
Watarase Research Center, Kyorin Pharmaceutical Co., Ltd. , 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Naoki
N
Ando
Watarase Research Center, Kyorin Pharmaceutical Co., Ltd. , 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Masahiro
M
Nomura
Watarase Research Center, Kyorin Pharmaceutical Co., Ltd. , 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Yasushi
Y
Kohno
Antibacterial; Gram-negative bacteria; LpxC; oxazolidinone; scaffold hopping