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) was written by Singh, Sheo B.;Kaelin, David E.;Wu, Jin;Miesel, Lynn;Tan, Christopher M.;Meinke, Peter T.;Olsen, David B.;Lagrutta, Armando;Wei, Changqing;Liao, Yonggang;Peng, Xuanjia;Wang, Xiu;Fukuda, Hideyuki;Kishii, Ryuta;Takei, Masaya;Yajima, Masanobu;Shibue, Taku;Shibata, Takeshi;Ohata, Kohei;Nishimura, Akinori;Fukuda, Yasumichi. And the article was included in Bioorganic & Medicinal Chemistry Letters in 2015.Category: pyridine-derivatives This article mentions the following:
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. Chem. 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 Me 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-Me 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. In the experiment, the researchers used many compounds, for example, 3-Fluoro-4-methylpyridine (cas: 399-88-2Category: pyridine-derivatives).
3-Fluoro-4-methylpyridine (cas: 399-88-2) belongs to pyridine derivatives. Pyridine is diamagnetic and has a diamagnetic susceptibility of −48.7 × 10−6 cm3·mol−1.The molecular electric dipole moment is 2.2 debyes. The standard enthalpy of formation is 100.2 kJ·mol−1 in the liquid phase and 140.4 kJ·mol−1 in the gas phase. Halopyridines are particularly attractive synthetic building blocks in a variety of cross-coupling methods, including the Suzuki-Miyaura cross-coupling reaction.Category: pyridine-derivatives