title: Hydroxy tricyclic 1,5-naphthyridinone oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents-SAR of RHS moiety (Part-3).
abstract: Novel bacterial topoisomerase inhibitors (NBTIs) are a new class of broad-spectrum antibacterial agents targeting bacterial Gyrase A and ParC and have potential utility in combating antibiotic resistance. (R)-Hydroxy-1,5-naphthyridinone left-hand side (LHS) oxabicyclooctane linked pyridoxazinone right-hand side (RHS) containing NBTIs showed a potent Gram-positive antibacterial profile. SAR around the RHS moiety, including substitutions around pyridooxazinone, pyridodioxane, and phenyl propenoids has been described. A fluoro substituted pyridoxazinone showed an MIC against Staphylococcus aureus of 0.5 μg/mL with reduced functional hERG activity (IC50 333 μM) and good in vivo efficacy [ED90 12 mg/kg, intravenous (iv) and 15 mg/kg, oral (p.o.)]. A pyridodioxane-containing NBTI showed a S. aureus MIC of 0.5 μg/mL, significantly improved hERG IC50 764 μM and strong efficacy of 11 mg/kg (iv) and 5 mg/kg (p.o.). A phenyl propenoid series of compounds showed potent antibacterial activity, but also showed potent hERG binding activity. Many of the compounds in the hydroxy-tricyclic series showed strong activity against Acinetobacter baumannii, but reduced activity against Escherichia coli and Pseudomonas aeruginosa. Bicyclic heterocycles appeared to be the best RHS moiety for the hydroxy-tricyclic oxabicyclooctane linked NBTIs.
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, United States. Electronic address: sheo.singh.215@gmail.com.
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: David E
authors.initials: DE
authors.lastname: Kaelin
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Jin
authors.initials: J
authors.lastname: Wu
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Lynn
authors.initials: L
authors.lastname: Miesel
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Tan
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Charles
authors.initials: C
authors.lastname: Gill
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Todd
authors.initials: T
authors.lastname: Black
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, United States.
authors.forename: Ravi
authors.initials: R
authors.lastname: Nargund
authors.affiliation: Merck Research Laboratories, Rahway 07065, United States.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Meinke
authors.affiliation: Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: David B
authors.initials: DB
authors.lastname: Olsen
authors.affiliation: Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Armando
authors.initials: A
authors.lastname: Lagrutta
authors.affiliation: WuXi AppTec, Shanghai, People's Republic of China.
authors.forename: Changqing
authors.initials: C
authors.lastname: Wei
authors.affiliation: WuXi AppTec, Shanghai, People's Republic of China.
authors.forename: Xuanjia
authors.initials: X
authors.lastname: Peng
authors.affiliation: WuXi AppTec, Shanghai, People's Republic of China.
authors.forename: Xiu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Fukuda
authors.affiliation: Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Kishii
authors.affiliation: Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Takei
authors.affiliation: Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takeuchi
authors.affiliation: Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Shibue
authors.affiliation: Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Ohata
authors.affiliation: Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Takano
authors.affiliation: Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Ban
authors.affiliation: Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Nishimura
authors.affiliation: Kyorin Pharmaceutical Co., Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan. Electronic address: yasumichi.fukuda@gmail.com.
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Fukuda
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D027081:DNA Gyrase / Q000737:chemistry / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D009287:Naphthyridines / Q000737:chemistry*; D010080:Oxazoles / Q000737:chemistry; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D059003:Topoisomerase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D009287:Naphthyridines; D010080:Oxazoles; D059003:Topoisomerase Inhibitors; C064210:oxazolidine; D027081:DNA Gyrase
keywords: Antibacterial; Bacterial topoisomerase inhibitors; Broad-spectrum; Gyrase inhibitors; Hydroxy tricyclic-1,5-naphthyridinone; ParC inhibitors