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

Abstract

In recent years, novel bacterial topoisomerase inhibitors (NBTIs) have been developed as future antibacterials for treating multidrug-resistant bacterial infections. A series of dioxane-linked NBTIs with an amide moiety has been synthesized and evaluated. Compound 3 inhibits DNA gyrase, induces the formation of single strand breaks to bacterial DNA, and achieves potent antibacterial activity against a variety of Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Optimization of this series of analogues led to the discovery of a subseries of compounds (22−25) with more potent anti-MRSA activity, dual inhibition of DNA gyrase and topoisomerase IV, and the ability to induce double strand breaks through inhibition of S. aureus DNA gyrase.

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. ,,,,,,, …”

“…aureus strains with target-based NBTI resistance. A previously reported ,,, strain with the D83N amino acid substitution in the GyrA domain of DNA gyrase served as the primary assay. Given the key role of D83 in binding NBTIs, such resistant strains have played a key role in the optimization of the NBTI class. ,,,,, Unsurprisingly, all of the compounds displayed elevated MICs with the D83N strain (Table ).…”

The Structural Features of Novel Bacterial Topoisomerase Inhibitors That Define Their Activity on Topoisomerase IV

“… 45 Replacing the amine with an amide group ( Figure 4 e, yellow) results in a noticeably weaker enzyme inhibition, as exemplified by compounds 28 and 29 ( Table S1 ). 45 , 46 …”

Synthesis of novel 2-methyl-3-furyl sulfide flavor derivatives as efficient preservatives

“…As amides oen possess certain bioactivity, the amide unit in these compounds (3d, 3e, 3f, 3g, 3h, 3i) may also help to improve the antimicrobial activity. [29][30][31][32] The cyclic ketone fragments in compounds 3j and 3l also enhance the antimicrobial activity in some cases. These results demonstrated that 2-methyl-3-furyl sulde avor derivatives have potential application prospects in the eld of food preservation, which is of great signicance for the prevention and control of foodborne microorganisms in the food industry or other industries.…”