Synthesis and anti-staphylococcal activity of novel bacterial topoisomerase inhibitors with a 5-amino-1,3-dioxane linker moiety

Dioxane-Linked Amide Derivatives as Novel Bacterial Topoisomerase Inhibitors against Gram-Positive Staphylococcus aureus

“…Consequently, significant effort has been devoted to reducing the basicity of the amine moiety to improve safety. Our initial approach was to reduce amine basicity with dioxygenated linkers derived either from 1,3-dioxane 23,25 or isomannide. 24 Matched pair comparisons of dioxane-linked (e.g., 2) and cyclohexane-linked NBTIs (e.g., 1) demonstrated consistent reductions in hERG inhibition, 23 illustrated in Figure 1.…”

“…Our initial approach was to reduce amine basicity with dioxygenated linkers derived either from 1,3-dioxane 23,25 or isomannide. 24 Matched pair comparisons of dioxane-linked (e.g., 2) and cyclohexane-linked NBTIs (e.g., 1) demonstrated consistent reductions in hERG inhibition, 23 illustrated in Figure 1. Nevertheless, achieving a lead-like hERG profile, with an IC 50 > 100 μM, has proved challenging.…”

“…On the whole, amide 3 shares a similar profile to our earlier reported dioxane-linked amine NBTIs, with promising activity against Gram-positive bacteria. 23,25 The promising antibacterial activity of 3 prompted us to characterize its mode of action in greater detail. NBTIs have generally been described to enhance gyrase-mediated single strand breaks (SSBs) to DNA without induction of double strand breaks (DSBs).…”

Novel Bacterial Topoisomerase Inhibitors: Challenges and Perspectives in Reducing hERG Toxicity

“…Novel bacterial topoisomerase inhibitors: challenges & perspectives in reducing hERG toxicity Editorial reduces functional hERG activity (IC 50 ≥ 30 μM) [18]. Moreover, the isosteric replacement of currently known linkers with a trans-dioxane scaffold seems to additionally contribute to the overall improved NBTIs hERG safety profile by reducing basicity and increasing polarity [19].…”

Stereoselective Acetalization for the Synthesis of Liquid-Crystal Compounds Possessing a trans-2,5-Disubstituted 1,3-Dioxane Ring with Saturated Aqueous Solutions of Inorganic Salts

“…The 1,3-dioxane ring is an important functional group found in biological active compounds, supramolecules, and fragrances as well as LC compounds, and this moiety also serves as a temporary protecting group for 1,3-diols, aldehydes, and ketones in chemical synthesis . In general, the 1,3-dioxane is formed by acetalization of the corresponding carbonyl compounds and 1,3-propanediols in the presence of an acid catalyst such as p -toluenesulfonic acid (TsOH) .…”