title: Structure activity relationship of C-2 ether substituted 1,5-naphthyridine analogs of oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-5).
abstract: Oxabicyclooctane linked novel bacterial topoisomerase inhibitors (NBTIs) are new class of recently reported broad-spectrum antibacterial agents. They target bacterial DNA gyrase and topoisomerase IV and bind to a site different than quinolones. They show no cross-resistance to known antibiotics and provide opportunity to combat drug-resistant bacteria. A structure activity relationship of the C-2 substituted ether analogs of 1,5-naphthyridine oxabicyclooctane-linked NBTIs are described. Synthesis and antibacterial activities of a total of 63 analogs have been summarized representing alkyl, cyclo alkyl, fluoro alkyl, hydroxy alkyl, amino alkyl, and carboxyl alkyl ethers. All compounds were tested against three key strains each of Gram-positive and Gram-negative bacteria as well as for hERG binding activities. Many key compounds were also tested for the functional hERG activity. Six compounds were evaluated for efficacy in a murine bacteremia model of Staphylococcus aureus infection. Significant tolerance for the ether substitution (including polar groups such as amino and carboxyl) at C-2 was observed for S. aureus activity however the same was not true for Enterococcus faecium and Gram-negative strains. Reduced clogD generally showed reduced hERG activity and improved in vivo efficacy but was generally associated with decreased overall potency. One of the best compounds was hydroxy propyl ether (16), which mainly retained the potency, spectrum and in vivo efficacy of AM8085 associated with the decreased hERG activity and improved physical property.
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: Peter T
authors.initials: PT
authors.lastname: Meinke
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, 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: 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: Tomoko
authors.initials: T
authors.lastname: Takeuchi
authors.affiliation: Kyorin Pharmaceutical Co., Ltd, 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Takano
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: Haruaki
authors.initials: H
authors.lastname: Kurasaki
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.
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. Electronic address: yasumichi.fukuda@gmail.com.
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Fukuda
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D034242:Cyclooctanes / Q000737:chemistry; D027081:DNA Gyrase / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D000072237:ERG1 Potassium Channel; D016984:Enterococcus faecium / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D009287:Naphthyridines / Q000737:chemistry*; D017207:Rats, Sprague-Dawley; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D034242:Cyclooctanes; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D009287:Naphthyridines; D059005:Topoisomerase II Inhibitors; D027081:DNA Gyrase
keywords: Antibacterial; Bacterial topoisomerase inhibitors; Broad-spectrum; Gyrase inhibitors; ParC inhibitors