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

Abstract

Aminoglycoside antibiotics target an internal RNA loop within the bacterial ribosomal decoding site. Here, we described 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. KeywordsAminoglycosides; Antibiotics; Translation inhibitors; 2-deoxy-streptamine; Ribosome; Decoding site; 3; 5-diamino-piperidine Bacterial resistance to antibiotics is on the rise and represents a global medical threat. In hospitals in the United States, approximately two million patients per year are infected. 1 The majority of these nosocomial pathogens are resistant to at least one antibiotic and result in about 90,000 deaths per year; a number that has increased 7-fold over the last decade. The recent and rapid spread of community acquired methicillin resistant Staphylococcus aureus further highlights the threat of resistance development and illustrates the need for new antibiotics that work by novel mechanisms. 2 Given the broad genetic and physiological diversity of bacterial pathogens and the need for empiric therapies that cover a broad panel of organisms, it is not surprising that discovery of new antibiotics has advanced slowly. Central to antibiotic discovery is identifying broadly validated targets. One such proven target is the bacterial ribosome, which is the target for a significant number of clinically important antibiotics that bind at the ribosomal RNA (rRNA). 3 Here, we expand on the description of a novel series of antibacterial compounds that target rRNA and blocks bacterial translation and growth. 4Three-dimensional structures of different aminoglycosides bound to the decoding site, or Asite, within the 16S rRNA have been determined by X-ray crystallography. 5 Importantly, these studies have shown that 2-deoxystreptamine (2-DOS), a conserved core scaffold among aminoglycosides, binds in a similar manner regardless of the 4,5-or 4,6-disubstitutions found in the neomycin or gentamicin families, respectively (Fig. 1) Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript groups of 2-DOS are predominantly involved in base recognition by forming conserved hydrogen bonds with A1493, G1494 and U1495 of the 16S rRNA. These interactions anchor the aminoglycoside scaffold within the A-site internal loop and displace residues A1492 and A1493 from the RNA interior. These two adenine residues act as a molecular switch that is involved in securing the fidelity of translation by interacting w...

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

“…A data set of 92 potent 1,3,5-triazine-2,4-diamine derivatives (TDA), reported to have antibacterial translation inhibitory activities were used for the following QSAR and Docking studies (Table 1) [10][11][12]. The data set and biological data of compounds were taken from literature, evaluated by similar group.…”

“…Recently, a set of potent 1,3,5-triazine-2,4-diamine derivatives (TDA) (Fig. 1) were prepared, similar to aminoglycoside compounds [10][11][12]. These novel aminoglycoside mimetics inhibit bacterial translation, presumably by interfering with the ribosomal decoding site (Asite) [10].…”

In vitro evaluation and in silico screening of synthetic acetylcholinesterase inhibitors bearing functionalized piperidine pharmacophores

“…4 A large number of compounds bearing piperidine scaffold have entered into preclinical and clinical trials over the last few years. 5 In particular, 1,4-disubstituted piperidine scaffolds find useful applications as established drugs such as donepezil (Aricept ® , an acetylcholinesterase inhibitor in the treatment of Alzheimer's disease), naratriptan (Naramig ® , an agonist of 5-hydroxytryptamine (serotonin) receptor 1D and 5-hydroxytryptamine receptor 1B in the treatment of migraine headaches), risperidone (Risperdal ® ) and sertindole (Serdolect ® ) (both nonselective 5-hydroxytryptamine receptor 2A/dopamine D 2 receptor (5-HT/D 2 ) antagonists, currently in the treatment of schizophrenia), 6,7 and exhibit anti-hypertensive, 8 antibacterial, 9 antimalarial, 10 anticonvulsant, and anti-inflammatory activities. 11 Moreover, some of them have been found to possess enzyme inhibitory activity against farnesyl transferase (FTase is believed to play an important role in development of progeria and various forms of cancers) 10 or dihydroorotate dehydrogenase (DHODH) 5 and also found to be useful in Parkinson's disease involving the MAO-based mechanism.…”

One-pot multicomponent synthesis of highly substituted piperidines using p-toluenesulfonic acid monohydrate as catalyst

“…Polyfunctionalized heterocyclic compounds play important roles in the drug discovery process and analysis of drugs in late development. Piperidines and their analogues have received attention owing to their biological activities [8,9], e.g., they act as antimalarial [10], antihypertensive [11], antibacterial [12], anticonvulsant, and anti-inflammatory agents [13]. As a result, various synthetic approaches have been developed for the synthesis of piperidines based on intramolecular Mannich reaction onto iminium ions [14], imino DielsAlder reaction [15,16], aza-Prins cyclizations [17,18], intramolecular Michael reaction [19], and cyclopropane ring-opening/Conia-ene cyclization [20].…”