title: Structure activity relationship of pyridoxazinone substituted RHS analogs of oxabicyclooctane-linked 1,5-naphthyridinyl novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-6).
abstract: Oxabicyclooctane linked 1,5-naphthyridinyl-pyridoxazinones are novel broad-spectrum bacterial topoisomerase inhibitors (NBTIs) targeting bacterial DNA gyrase and topoisomerase IV at a site different than quinolones. Due to lack of cross-resistance to known antibiotics they present excellent opportunity to combat drug-resistant bacteria. A structure activity relationship of the pyridoxazinone moiety is described in this Letter. Chemical synthesis and activities of NBTIs with substitutions at C-3, C-4 and C-7 of the pyridoxazinone moiety with halogens, alkyl groups and methoxy group has been described. In addition, substitutions of the linker NH proton and its transformation into amide analogs of AM-8085 and AM-8191 have been reported. Fluoro, chloro, and methyl groups at C-3 of the pyridoxazinone moiety retained the potency and spectrum. In addition, a C-3 fluoro analog showed 4-fold better oral efficacy (ED50 3.9 mg/kg) as compared to the parent AM-8085 in a murine bacteremia model of infection of Staphylococcus aureus. Even modest polarity (e.g., methoxy) is not tolerated at C-3 of the pyridoxazinone unit. The basicity and NH group of the linker is important for the activity when CH2 is at the linker position-8. However, amides (with linker position-8 ketone) with a position-7 NH or N-methyl group retained potency and spectrum suggesting that neither basicity nor hydrogen-donor properties of the linker amide NH is essential for the activity. This would suggest likely an altered binding mode of the linker position-7,8 amide containing compounds. The amides showed highly improved hERG (functional IC50 >30 μM) profile.
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: 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: Yonggang
authors.initials: Y
authors.lastname: Liao
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, 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Fukuda
authors.affiliation: Kyorin Pharmaceutical Co., Ltd, 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Kishii
authors.affiliation: Kyorin Pharmaceutical Co., Ltd, 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Takei
authors.affiliation: Kyorin Pharmaceutical Co., Ltd, 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Yajima
authors.affiliation: Kyorin Pharmaceutical Co., Ltd, 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Shibue
authors.affiliation: Kyorin Pharmaceutical Co., Ltd, 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Kyorin Pharmaceutical Co., Ltd, 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Ohata
authors.affiliation: Kyorin Pharmaceutical Co., Ltd, 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Nishimura
authors.affiliation: Kyorin Pharmaceutical Co., Ltd, 1848 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: D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D034242:Cyclooctanes / Q000737:chemistry*; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects / Q000472:pathogenicity; D013329:Structure-Activity Relationship; D059003:Topoisomerase Inhibitors / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C000607675:AM-8085; C000607673:AM-8191; D000900:Anti-Bacterial Agents; D034242:Cyclooctanes; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006574:Heterocyclic Compounds, 2-Ring; D009287:Naphthyridines; D059003:Topoisomerase Inhibitors; D027101:DNA Topoisomerase IV
keywords: Antibacterial; Bacterial topoisomerase inhibitors; Broad-spectrum; Gyrase inhibitors; ParC inhibitors