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.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Cyclooctanes/chemistry , Drug Evaluation, Preclinical/methods , Structure-Activity Relationship , Topoisomerase Inhibitors/chemistry , Administration, Oral , Animals , Anti-Bacterial Agents/administration & dosage , Chemistry Techniques, Synthetic , DNA Topoisomerase IV/antagonists & inhibitors , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/metabolism , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/pharmacology , Mice , Microbial Sensitivity Tests , Naphthyridines/chemistry , Naphthyridines/pharmacology , Staphylococcal Infections/drug therapy , Staphylococcus aureus/drug effects , Staphylococcus aureus/pathogenicity , Topoisomerase Inhibitors/pharmacologyABSTRACT
[reaction: see text] 13-Hydroxy-14-nordehydrocacalohastine (2) and 13-acetoxy-14-nordehydrocacalohastine (3), two novel modified furanoeremophilane-type sesquiterpenes isolated from Trichilia cuneata, showed inhibitory activities for membrane lipid peroxidation in mitochondria and microsomes. The first, highly convergent total syntheses of new compounds 2 and 3 have also been achieved via a palladium-mediated three-component coupling reaction between 2-iodotoluene (7), 1-penten-4-yn-3-ol (8), and diethyl ethoxymethylenemalonate (9).