Aminoglycoside Mimetics Research Articles

Epoxide Ring-Opening Reactions of Two Diastereomeric 1,2- Epoxy-3-(N-benzyl-N-methylamino)cycloheptanes

Background: Cyclic amino alcohols comprise one of the most important functional motifs of aminoglycoside-type antibiotics. Development of the strategies towards new cyclic amino alcohols allows a broader investigation of these compounds in biology and medicine. Much attention is paid to the preparation of aminoglycoside mimetics that have simpler structures, but retain the biological activity of parent structures. Oxirane ring opening is a synthetically significant reaction for the creation of new pharmaceutically important scaffolds. A distinguishing feature of this approach is the synthesis of amino alcohols with the assigned stereochemistry. Regio- and stereochemical diversity within a sugar-like moiety in those mimetics may subtly influence their biological activity. We propose a regio- and stereospecific route towards trisubstituted cycloheptanes. Methods: Initially, two diastereomeric 1,2-epoxy-3-(N-benzyl-N-methylamino)cycloheptanes with opposite orientation of the oxirane ring to the amino moiety were synthesized. Then, epoxide ring-opening reactions with different nucleophiles under acid- or base-catalyzed conditions were performed. The structure of the products was confirmed by two dimentional NMR methods. Results: Three types of regioisomers, according to the direction of the nucleophilic attack, were obtained. The regio- and stereoselective outcome of these reactions depends on the relative orientation of the oxirane ring and the nature of the catalyst. Conclusion: In summary, the regio- and stereospecific outcome of the epoxide ring cleavage of 1,2-epoxy-3- substituted cycloheptanes was highlighted. The route allows to synthesize new regio- and stereochemically diverse aminocycloheptanol derivatives on multi-gram scale, which could serve as prospective building blocks for the aminoglycoside antibiotic research. The benzyl removal and the further functionalization of nitrogen atom could provide the creation of novel scaffolds for the pharmaceutical and biotech research communities. Keywords: Aminoglycoside mimetic, aminocycloheptanol, epoxide, ring cleavage, stereoselectivity, regioselectivity.

Orthogonally Protected Furanoid Sugar Diamino Acids for Solid-Phase Synthesis of Oligosaccharide Mimetics.

Sugar diamino acids (SDAs), which differ from the widely used sugar amino acids in the presence of a second amino group connected to the carbohydrate core, share structural features of both amino acids and carbohydrates. They can be used for the preparation of linear and branched amide-linked oligosaccharide mimetics. Such oligomers carry free amino groups, which are positively charged at neutral pH, in a spatially defined way and, thus, represent a potential class of aminoglycoside mimetics. We report here the first examples of orthogonally protected furanoid SDAs and their use in solid-phase synthesis. Starting from d-glucose, we developed a divergent synthetic route to three derivatives of 3,5-diamino-3,5-dideoxy-d-ribofuranose. These building blocks are compatible with solid-phase peptide synthesis following the 9-fluorenylmethoxycarbonyl (Fmoc) strategy, which we demonstrate by the synthesis of an SDA tetramer.

The Use of Structure-Guided Design to Discover New Anti-Microbial Agents: Focus on Antibacterial Resistance

Serious attempts to address antibiotic resistance, a worldwide public health concern, have recently become more intensive. In hospital settings, resistance to antibacterial agents has been recognized by clinicians for several decades. Resistant strains are now isolated on a daily basis from patients with community-acquired infections further elevating the level of concern among public health officials. The pharmaceutical industry has generally focused its attentions on chronic therapeutic indications in recent years (e.g. cardiovascular and metabolic diseases), but will likely be forced to reengage in antibacterial discovery efforts as therapeutic options diminish for the treatment of infections caused by multidrug resistant pathogens. The ability to squeeze additional utility out of known classes of antibacterial agents has become limited and antibacterial discovery scientists will need to focus on new approaches and targets. These new approaches will need to include strategies that explicitly address resistance up front and simultaneously attempt to facilitate the slower development of resistance as new compound classes enter clinical use. One approach that can be a useful component of antibacterial discovery efforts and prospectively address resistance is structure-guided design (SGD). This review will describe several recent examples in which SGD was applied as part of a multidisciplinary effort to address antibacterial resistance. These include dihydrofolate reductase inhibitors, broad-spectrum β-lactamase inhibitors, novel oxazolidinones, aminoglycoside mimetics, peptide deformylase inhibitors, and inhibitors that simultaneously target DNA gyrase and topoisomerase IV. Keywords: Antibiotic resistance, antibiotic drug discovery, resistance mechanisms, structure-guided design, dual targeting

Antibacterial activity in serum of the 3,5-diamino-piperidine translation inhibitors

Translation inhibitors of the 3,5-diamino-piperidine series act as aminoglycoside mimetics that inhibit bacterial growth. Here we show antibacterial SAR in the presence and absence of serum with a particular focus toward Pseudomonas aeruginosa.

3D-QSAR and molecular docking studies of 1,3,5-triazene-2,4-diamine derivatives against r-RNA: Novel bacterial translation inhibitors

Aminoglycoside mimetics inhibit bacterial translation by interfering with the ribosomal decoding site. To elucidate the structural properties of these compounds important for antibacterial activity, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied to a set of 56 aminoglycosides mimetics. The successful CoMFA model yielded the leave-one-out (LOO) cross-validated correlation coefficient ( q 2) of 0.708 and a non-cross-validated correlation coefficient ( r 2) of 0.967. CoMSIA model gave q 2 = 0.556 and r 2 = 0.935. The CoMFA and CoMSIA models were validated with 36 test set compounds and showed a good r pred 2 of 0.624 and 0.640, respectively. Contour maps of the two QSAR approaches show that electronic effects dominantly determine the binding affinities. These obtained results were agreed well with the experimental observations and docking studies. The results not only lead to a better understanding of structural requirements of bacterial translation inhibitors but also can help in the design of novel bacterial translation inhibitors.

New Insights into Aminoglycoside Antibiotics and Derivatives

In the post-genome era, RNA has emerged as a valid molecular target involved in many biochemical pathways such as cellular protein interactions. This includes transcription and translation, HIV-Rev and HIV-tat proteins binding to HIV RNA that encode HIV genetic information. The binding of natural and synthetic aminoglycosides to RNA or RNA-protein complexes has been a central focus of small molecules-RNA recognition events, since they bind selectively to a variety of RNA targets. The understanding of the contribution of shape-based and charge motifs involved in aminoglycosides-RNA complexes gives remarkable information of the translational miscoding process, thereby opening new insights for drug discovery. This review comprises relevant information about aminoglycosides antibiotics, including chemical structure, molecular mechanism, structure-activity relationships, recent advances in aminoglycoside mimetics over the last four years, resistance mechanisms and structure-toxicity relationships.

Synthesis and SAR of 3,5-diamino-piperidine derivatives: Novel antibacterial translation inhibitors as aminoglycoside mimetics

Aminoglycoside antibiotics target an internal RNA loop within the bacterial ribosomal decoding site. Here, we describe the synthesis and SAR of novel 3,5-diamino-piperidine derivatives as aminoglycoside mimetics, and show they act as inhibitors of bacterial translation and growth.

Structure-Guided Discovery of Novel Aminoglycoside Mimetics as Antibacterial Translation Inhibitors

We report the structure-guided discovery, synthesis, and initial characterization of 3,5-diamino-piperidinyl triazines (DAPT), a novel translation inhibitor class that targets bacterial rRNA and exhibits broad-spectrum antibacterial activity. DAPT compounds were designed as structural mimetics of aminoglycoside antibiotics which bind to the bacterial ribosomal decoding site and thereby interfere with translational fidelity. We found that DAPT compounds bind to oligonucleotide models of decoding-site RNA, inhibit translation in vitro, and induce translation misincorporation in vivo, in agreement with a mechanism of action at the ribosomal decoding site. The novel DAPT antibacterials inhibit growth of gram-positive and gram-negative bacteria, including the respiratory pathogen Pseudomonas aeruginosa, and display low toxicity to human cell lines. In a mouse protection model, an advanced DAPT compound demonstrated efficacy against an Escherichia coli infection at a 50% protective dose of 2.4 mg/kg of body weight by single-dose intravenous administration.

Synthesis of polynitrogenated analogues of glucopyranoses from levoglucosan

Polynitrogenated analogues of glucopyranoses were synthesised from levoglucosan. These compounds are useful intermediates for the synthesis of new aminoglycoside mimetics.

Design and Synthesis of Paromomycin‐Related Heterocycle‐Substituted Aminoglycoside Mimetics Based on a Mass Spectrometry RNA‐Binding Assay.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of Carbohydrate‐Based Antibiotics

AbstractFor Abstract see ChemInform Abstract in Full Text.

Novel acyclic deoxystreptamine mimetics targeting the ribosomal decoding site.

Two scaffolds, one target: The bacterial ribosomal decoding site is the target for natural aminoglycoside antibiotics, which bind to an internal RNA loop and thereby interfere with translation fidelity. Synthetic aminoglycoside mimetics are thought to display similar antibiotic activity while avoiding established bacterial resistance mechanisms. We describe two complementary approaches towards novel aminoglycoside mimetics that recognize the decoding-site RNA and inhibit bacterial translation. In the first study, elements of both rational structure-based design and diversity-driven exploration were used to synthesize flexible acyclic mimetics (I a,b) of 2-deoxystreptamine. The second paper outlines the accurate replacement of the 2-deoxystreptamine pharmacophore by stereochemically defined aminomethyl–piperidine scaffolds (II a,b).

Design and synthesis of paromomycin-related heterocycle-substituted aminoglycoside mimetics based on a mass spectrometry RNA-binding assay.

A good starting point for the design of potent bactericidal compounds is the aminoglycoside paromomycin (1). The A-ring (shown in red) was replaced with a range of heterocycles. An ESIMS-based RNA-binding assay was used to screen the binding affinities of the products.

Discovery of aminoglycoside mimetics by NMR-based screening of Escherichia coli A-site RNA.

A method is described for the NMR-based screening for the discovery of aminoglycoside mimetics that bind to Escherichia coli A-site RNA. Although aminoglycosides are clinically useful, they exhibit high nephrotoxicity and ototoxicity, and their overuse has led to the development of resistance to important microbial pathogens. To identify a new series of aminoglycoside mimetics that could potentially overcome the problems associated with toxicities and resistance development observed with the aminoglycosides, we have prepared large quantities of E. coli 16 S A-site RNA and conducted an NMR-based screening of our compound library in search for small-molecule RNA binders against this RNA target. From these studies, several classes of compounds were identified as initial hits with binding affinities in the range of 70 microM to 3 mM. Lead optimization through synthetic modifications of these initial hits led to the discovery of several small-molecule aminoglycoside mimetics that are structurally very different from the known aminoglycosides. Structural models of the A-site RNA/ligand complexes were prepared and compared to the three-dimensional structures of the RNA/aminoglycoside complexes.

Synthesis of carbohydrate-based antibiotics

Abstract Tackling the problem of carbohydrate recognition is a subject of current interest. Our strategies in this regard include development of new methods for the synthesis of saccharides and sugar arrays for screening, design of d-peptides to target bacterial cell-surface sugars, preparation of mechanism-based inhibitors of the enzymes involved in the biosynthesis of saccharides and the synthesis of aminoglycoside mimetics to target RNA.

Aminoglycoside mimetics as small-molecule drugs targeting RNA.

The potential of RNA as a new drug target has recently come to the fore, with the recognition that RNA molecules can adopt complex three-dimensional structures that, as with proteins, enable the design of specific ligands. Another reason for the present interest comes from the fact that many pathogenic agents, such as retroviruses, encode their genetic information in RNA strands. Unfortunately, the high toxicity and rapid emergence of high-level resistance have severely limited the usefulness of naturally occurring aminoglycoside antibiotics. To tackle these problems, it is an important concern to design new synthetic compounds with smaller, simpler structures which possess higher RNA binding affinity, better selectivity, better antibiotic activity, and stronger resistance against the aminoglycoside-modifying enzymes compared to their parent structures. Here, we will attempt a survey of current efforts to develop aminoglycoside mimetics or derivatives that target RNA. The latest advances in this field including rational design, synthetic strategy, and structure activity relationships are reviewed.

A Library Approach to the Discovery of Small Molecules That Recognize RNA: Use of a 1,3-Hydroxyamine Motif as Core

A library of compounds based upon an aminoglucopyranoside core has been developed and screened for binding to RNA and specifically to 16S ribosomal RNA. The title molecules simplify the complexity of naturally occurring aminoglycoside antibiotics by embodying a putative recognition motif found within these structures, namely, a 1,3-hydroxyamine. The core pyranoside bearing the hydroxyamine motif was structurally varied at two points through a combinatorial approach utilizing acylation and reductive amination protocols. The aminoglycoside mimetics were screened in an automated assay based upon surface plasmon resonance (SPR), and some were found effective at binding a 27-nucleotide model (AS-wt) of A-site 16S RNA as well as a drug-resistant mutant RNA in the micromolar range.