Structurally Optimized Potent Dual-Targeting NBTI Antibacterials with an Enhanced Bifurcated Halogen-Bonding Propensity

Abstract

We designed and synthesized an optimized library of novel bacterial topoisomerase inhibitors with p -halogenated phenyl right-hand side fragments and significantly enhanced and balanced dual-targeted DNA gyrase and topoisomerase IV activities of Staphylococcus aureus and Escherichia coli . By increasing the electron-withdrawing properties of the p -halogenated phenyl right-hand side fragment and maintaining a similar lipophilicity and size, an increased potency was achieved, indicating that the antibacterial activities of this series of novel bacterial topoisomerase inhibitors against all target enzymes are determined by halogen-bonding rather than van der Waals interactions. They show nanomolar enzyme inhibitory and whole-cell antibacterial activities against S. aureus and methicillin-resistant S. aureus (MRSA) strains. However, due to the relatively high substrate specificity for the bacterial efflux pumps, they tend to be less potent against E. coli and other Gram-negative pathogens.

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

“…As a continuation of this work, we also demonstrated that the inhibitory potencies of NBTIs with p -halogenated phenyl RHS fragments can be enhanced by increasing their electron-withdrawing properties as well as halogen-bonding propensities, while maintaining the same lipophilicity and approximately the same RHS size ( Table S1 , 47 , 49 , and 50 ). 41 Put differently, the flexibility provided by replacement of a bicyclic heteroaromatic RHS moiety with a monocyclic one (e.g., a halogenated phenyl) and its suitable length are crucial to establish halogen-bonding interactions with the Ala residues and result in a stronger enzyme inhibition. 38 Moreover, the replacement of triazole with pyrazole ( Figure 5 f, blue) generally leads to increased inhibitory potency.…”

“… (a) An E. coli topoIV protein homology model showing a predicted binding pose of an NBTI (compound 8 from Kokot et al 41 ). The topoIV enzyme and DNA are represented as cartoons (ParC subunit in green, ParE subunit in purple, DNA in orange).…”

“…We are aware that the different assay formats for determining topoIV inhibition by the NBTIs reviewed in this perspective are not directly comparable to each other. For instance, the topoIV decatenation assay was performed in refs , ,, − , the DNA topoIV relaxation assay was used in refs , , , , , and , while the ATPase activity of E. coli ParE subunit was determined in refs and − . The comparison of two different assays (e.g., DNA Cleavage and topoIV DNA Decatenation) for the same compounds , showed that the relative potency of a given compound can be different depending on the assay used.…”

Diminishing hERG inhibitory activity of aminopiperidine-naphthyridine linked NBTI antibacterials by structural and physicochemical optimizations

“…In our previous studies, we improved the antibacterial activity of our series of aminopiperidine-naphthyridine linked NBTIs comprising phalogenated phenyl RHS fragments by strengthening the halogenbonding propensity on the enzyme binding side [17,38,39]. Indeed, this structural optimization yielded NBTIs with excellent antibacterial activities and enzyme inhibitory potencies, but with notable hERG inhibition that remains a major issue.…”

Intrinsic Bond Strength Index as a halogen bond interaction energy predictor

“…There have been attempts to overcome this challenge and provide a solid basis for designing new halogen-bonded structures 8,21,[26][27][28] , but accurate modelling of XBs is still not straightforward. This issue is paramount given the increased attention put on XBs and and their broad application in catalysis 19,[29][30][31][32] , material design [33][34][35] , supramolecular [36][37][38] and medicinal [39][40][41] chemistry, among other areas.…”