Novel bacterial topoisomerase inhibitors derived from isomannide

Optimization of TopoIV Potency, ADMET Properties, and hERG Inhibition of 5-Amino-1,3-dioxane-Linked Novel Bacterial Topoisomerase Inhibitors: Identification of a Lead with In Vivo Efficacy against MRSA

“…Mutations encoding the D83N and M121K amino acid substitutions were observed for each compound. Such mutations are consistent with the observed binding mode for compound 7 (Figure ) as well as with earlier reports that these sites constituted important loci of resistance to NBTIs. ,,,,,,, …”

“…Potent antibacterial activity was likewise demonstrated against a variety of Gram-positive bacteria, including key multidrug-resistant pathogens such as MRSA and vancomycin-resistant Enterococci (VRE). Dioxane-linked NBTIs are more potent than a series of NBTIs with a dioxygenated linker derived from isomannide . Consequently, we selected the dioxane-linked series for optimization efforts directed at five key objectives: (1) maintaining or improving whole-cell antibacterial activity, especially against MRSA, (2) enhancing TopoIV inhibition, (3) increasing potency against NBTI-resistant S.…”

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

“…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.…”

“…Analysis of ternary X-ray crystal structures ,, with NBTIs, DNA, and S. aureus gyrase reveal a key interaction between this amine nitrogen and an aspartate (D83) located at the entrance to a small hydrophobic binding pocket formed at the interface of two GyrA domains. Studies on acquired resistance to NBTIs support the relevance of this interaction; D83N and D83G substitutions are among the most commonly reported NBTI resistance determinants in S. aureus . − Unfortunately, the basicity of the amine moiety of the NBTIs has been correlated with hERG inhibition, − an adverse in vitro safety finding. Consequently, significant effort has been devoted to reducing the basicity of the amine moiety to improve safety.…”

“…Minimum inhibitory concentrations (MICs) were determined using S. aureus ATCC 29213 and a ciprofloxacin-resistant USA300 MRSA isolate, as reported previously. − Select compounds, including all analogues with MICs ≤ 2 μg/mL, were tested using biochemical gel-based assays for inhibition of S. aureus gyrase supercoiling and TopoIV decatenation activity. We also measured MICs using a previously reported , NBTI-resistant strain of S. aureus with the gyrase D83N substitution alongside the otherwise isogenic parent strain bearing the canonical aspartate (strain 3527).…”