Second generation analogs of rigid 6,7-spiro scaffolds targeting the bacterial ribosome

Recent Advances in Developing Small Molecules Targeting RNA

“…These derivatives have increased affinities for the A-site and/or reduced affinity for aminoglycoside-modifying enzymes . Recently, Vourloumis and co-workers developed spiro-compouds ( 1 – 3 , Figure ) utilizing the 2-deoxystreptamine (2-DOS) scaffold (Figure ), the core building block (ring II) of neomycin and paromomycin (Figure ) . Using a fluorescence-based assay, the half-maximal response concentration (EC 50 values) of these compounds for binding to the A-site were determined to be in the micromolar range.…”

Synthesis of 5,6‐Spiroethers and Evaluation of their Affinities for the Bacterial A Site

“…Of the monosubstituted analogues, the alcohol 13 represents the strongest binder, with affinity in the lownm concentrations. This significant improvement relative to previously reported rigid spiroether analogues [7,8] motivated a computational modelling attempt to interpret their atomiclevel interactions with the A-site.…”

“…[5] Despite the challenges that still confront the discovery and pharmacological application of new aminoglycoside conjugates, the potential of such chemical entities to interfere with diverse biological processes remains highly attractive. [6] Our past endeavours in this field have focused on the synthesis and biological evaluation of rigid spirocyclic ethers [7,8] that appear to capture the "bioactive" conformation within the A site of the ribosomal RNA (Scheme 1). In order to explore the chemical space that can be accessed by these means further, cyclic 5,6-spiroethers bearing triazole moieties were readily synthesized and assessed for their binding potentials.…”

“…[10] Moreover, triazoles have unique biological potential, possibly arising from p stacking with other aromatic [11] or carbohydrate moieties [3] of the RNA target, and therefore comprise an important pharmacophore for potential drug discovery. [12] A noteworthy difference from past synthetic analogues of the same chemical family [7,8] is the substitution pattern of the spiroether. The presented compounds are extended in their "northwestern" flanks with a set of functionalities that can satisfy and complement the condition of "structural electrostatic complementarity" [4] within the active site.…”

“…Docking of compounds 7-18 into a model of the rRNA A-site was performed as described previously. [7,8] The calculated conformations of the most potent compound 13 exhibit a high degree of invariability with respect to its orientation within the A-site. This was also evident for all spiroether triazole compounds, because their docking to the decoding centre predicted at least four major clusters of putative orientations.…”