Structure activity relationship of substituted 1,5-naphthyridine analogs of oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-4).
Bacterial resistance is rapidly growing, necessitating the need to discover new agents. Novel bacterial topoisomerase inhibitors (NBTIs) are new class of broad-spectrum antibacterial agents targeting bacterial DNA gyrase and topoisomerase IV. This class of inhibitors binds to an alternative binding site relative to fluoroquinolones and shows no cross-resistance to quinolones. NBTIs consist of three structural motifs. A structure activity relationship of the left hand motif 1,5-naphthyridine of oxabicyclooctane-linked NBTIs is described. Fifty five compounds were evaluated against a panel of key Gram-positive and Gram-negative strains of bacteria, as well as for hERG activity and five compounds were tested for in vivo efficacy in murine model of Staphylococcus aureus infection. These studies suggest that only a narrow range (activating and deactivating) of substitutions at C-2 and C-7 are tolerated for optimal antibacterial activity and spectrum. An alkoxy (methoxy) and CN at C-2, and a halogen and hydroxyl at C-7, appeared to be preferred in this series. Substitutions on the other three carbons generally have detrimental effect on the activity. No clear hERG activity SAR emerged from these substitutions.
Merck Research Laboratories, Kenilworth, NJ 07033, United States. Electronic address: sheo.singh.215@gmail.com.
Sheo B
SB
Singh
Merck Research Laboratories, Kenilworth, NJ 07033, United States.
David E
DE
Kaelin
Merck Research Laboratories, Kenilworth, NJ 07033, United States.
Jin
J
Wu
Merck Research Laboratories, Kenilworth, NJ 07033, United States.
Lynn
L
Miesel
Merck Research Laboratories, Kenilworth, NJ 07033, United States.
Christopher M
CM
Tan
Merck Research Laboratories, Kenilworth, NJ 07033, United States.
Peter T
PT
Meinke
Merck Research Laboratories, West Point, PA 19486, United States.
David B
DB
Olsen
Merck Research Laboratories, West Point, PA 19486, United States.
Armando
A
Lagrutta
WuXi AppTec, Shanghai, People's Republic of China.
Changqing
C
Wei
WuXi AppTec, Shanghai, People's Republic of China.
Xuanjia
X
Peng
WuXi AppTec, Shanghai, People's Republic of China.
Xiu
X
Wang
Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Hideyuki
H
Fukuda
Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Ryuta
R
Kishii
Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Masaya
M
Takei
Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Takeshi
T
Shibata
Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Kohei
K
Ohata
Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Hisashi
H
Takano
Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Haruaki
H
Kurasaki
Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Tomoko
T
Takeuchi
Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Akinori
A
Nishimura
Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan. Electronic address: yasumichi.fukuda@gmail.com.
Yasumichi
Y
Fukuda
D000818:Animals; D026942:DNA Topoisomerases / Q000378:metabolism*; D051379:Mice; D015394:Molecular Structure; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D059003:Topoisomerase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
D059003:Topoisomerase Inhibitors; D026942:DNA Topoisomerases
Antibacterial; Bacterial topoisomerase inhibitors; Broad-spectrum; Gyrase inhibitors; ParC inhibitors