title: Tricyclic 1,5-naphthyridinone oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents-SAR of left-hand-side moiety (Part-2).
abstract: Novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of broad-spectrum antibacterial agents targeting bacterial Gyrase A and ParC and have potential utility in combating antibiotic resistance. A series of novel oxabicyclooctane-linked NBTIs with new tricyclic-1,5-naphthyridinone left hand side moieties have been described. Compounds with a (R)-hydroxy-1,5-naphthyridinone moiety (7) showed potent antibacterial activity (e.g., Staphylococcus aureus MIC 0.25 μg/mL), acceptable Gram-positive and Gram-negative spectrum with rapidly bactericidal activity. The compound 7 showed intravenous and oral efficacy (ED50) at 3.2 and 27 mg/kg doses, respectively, in a murine model of bacteremia. Most importantly they showed significant attenuation of functional hERG activity (IC50 >170 μM). In general, lower logD attenuated hERG activity but also reduced Gram-negative activity. The co-crystal structure of a hydroxy-tricyclic NBTI bound to a DNA-gyrase complex exhibited a binding mode that show enantiomeric preference for R isomer and explains the activity and SAR. The discovery, synthesis, SAR and X-ray crystal structure of the left-hand-side tricyclic 1,5-naphthyridinone based oxabicyclooctane linked NBTIs are described.
authors: Merck Research Laboratories, Kenilworth, NJ 07033, United States. Electronic address: sheo.singh.215@gmail.com.
authors: Sheo B
authors: SB
authors: Singh
authors: Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors: David E
authors: DE
authors: Kaelin
authors: Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors: Jin
authors: J
authors: Wu
authors: Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors: Lynn
authors: L
authors: Miesel
authors: Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors: Christopher M
authors: CM
authors: Tan
authors: Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors: Todd
authors: T
authors: Black
authors: Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors: Ravi
authors: R
authors: Nargund
authors: Merck Research Laboratories, Rahway 07065, United States.
authors: Peter T
authors: PT
authors: Meinke
authors: Merck Research Laboratories, West Point, PA 19486, United States.
authors: David B
authors: DB
authors: Olsen
authors: Merck Research Laboratories, West Point, PA 19486, United States.
authors: Armando
authors: A
authors: Lagrutta
authors: Merck Research Laboratories, West Point, PA 19486, United States.
authors: Jun
authors: J
authors: Lu
authors: Merck Research Laboratories, West Point, PA 19486, United States.
authors: Sangita
authors: S
authors: Patel
authors: Merck Research Laboratories, West Point, PA 19486, United States.
authors: Keith W
authors: KW
authors: Rickert
authors: Merck Research Laboratories, West Point, PA 19486, United States.
authors: Robert F
authors: RF
authors: Smith
authors: Merck Research Laboratories, West Point, PA 19486, United States.
authors: Stephen
authors: S
authors: Soisson
authors: Merck Research Laboratories, Rahway 07065, United States.
authors: Edward
authors: E
authors: Sherer
authors: Merck Research Laboratories, Rahway 07065, United States.
authors: Leo A
authors: LA
authors: Joyce
authors: WuXi AppTec, Shanghai, People's Republic of China.
authors: Changqing
authors: C
authors: Wei
authors: WuXi AppTec, Shanghai, People's Republic of China.
authors: Xuanjia
authors: X
authors: Peng
authors: WuXi AppTec, Shanghai, People's Republic of China.
authors: Xiu
authors: X
authors: Wang
authors: Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors: Hideyuki
authors: H
authors: Fukuda
authors: Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors: Ryuta
authors: R
authors: Kishii
authors: Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors: Masaya
authors: M
authors: Takei
authors: Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors: Hisashi
authors: H
authors: Takano
authors: Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors: Mitsuhito
authors: M
authors: Shibasaki
authors: Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors: Masanobu
authors: M
authors: Yajima
authors: Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors: Akinori
authors: A
authors: Nishimura
authors: Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors: Takeshi
authors: T
authors: Shibata
authors: Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan. Electronic address: yasumichi.fukuda@gmail.com.
authors: Yasumichi
authors: Y
authors: Fukuda
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D034242:Cyclooctanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000201:enzymology; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009287:Naphthyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000604974:1,5-naphthyridinone oxabicyclooctane; D000900:Anti-Bacterial Agents; D034242:Cyclooctanes; D009287:Naphthyridines; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II
keywords: Antibacterial; Bacterial topoisomerase inhibitors; Broad-spectrum; Gyrase inhibitors; ParC inhibitors; Tricyclic-1,5-naphthyridinone