Referenced in: none

Automatically associated channels: Kv11.1

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).

Authors: Sheo B Singh, David E Kaelin, Jin Wu, Lynn Miesel, Christopher M Tan, Peter T Meinke, David B Olsen, Armando Lagrutta, Changqing Wei, Yonggang Liao, Xuanjia Peng, Xiu Wang, Hideyuki Fukuda, Ryuta Kishii, Masaya Takei, Masanobu Yajima, Taku Shibue, Takeshi Shibata, Kohei Ohata, Akinori Nishimura, Yasumichi Fukuda

Journal, date & volume: Bioorg. Med. Chem. Lett., 2015 Sep 1 , 25, 3636-43

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/26141771

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.