Exploring 9-benzyl purines as inhibitors of glutamate racemase (MurI) in Gram-positive bacteria

Geng, Bin; Breault, Gloria A.; Comita-Prevoir, Janelle; Petrichko, Randy; Eyermann, Charles J.; Lundqvist, T.; Doig, P.; Gorseth, Elise; Noonan, Brian

doi:10.1016/j.bmcl.2008.06.068

Cited by 21 publications

(18 citation statements)

References 18 publications

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“…In this particular case we note that a close homolog, glutamate racemase from Helicobacter pylori, has potent and druglike non-competitive inhibitors that bind to the corresponding site. 90,91 …”

Section: Introductionmentioning

confidence: 99%

New Frontiers in Druggability

Kozakov

Hall

Napoleon³

et al. 2015

J. Med. Chem.

162

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A powerful early approach to evaluating the druggability of proteins involved determining the hit rate in NMR-based screening of a library of small compounds. Here we show that a computational analog of this method, based on mapping proteins using small molecules as probes, can reliably reproduce druggability results from NMR-based screening, and can provide a more meaningful assessment in cases where the two approaches disagree. We apply the method to a large set of proteins. The results show that, because the method is based on the biophysics of binding rather than on empirical parameterization, meaningful information can be gained about classes of proteins and classes of compounds beyond those resembling validated targets and conventionally druglike ligands. In particular, the method identifies targets that, while not druggable by druglike compounds, may become druggable using compound classes such as macrocycles or other large molecules beyond the rule-of-five limit.

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Section: Introductionmentioning

confidence: 99%

New Frontiers in Druggability

Kozakov

Hall

Napoleon³

et al. 2015

J. Med. Chem.

162

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“…The difference in the electrophilicity between the C2 and C6 carbons of nucleoside 71 was exploited to synthesize aminochloride 72 , in 93% yield, via displacement of the C6 chlorine residue with benzylamine. 25 Cyclization induced by NaOH then afforded, through the corresponding hydroxy tosylate, locked nucleoside 73 in 68% yield. Desilylation of the latter compound produced alcohol 33 (HF·py, 96% yield), and subsequent debenzylation of compound 33 (MsOH) furnished diol analogue 34 (61% yield).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and biological evaluation of 2′,4′- and 3′,4′-bridged nucleoside analogues

Nicolaou

Ellery

Rivas

et al. 2011

Bioorganic & Medicinal Chemistry

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Most nucleosides in solution typically exist in equilibrium between two major sugar pucker forms, N-type and S-type, but bridged nucleosides can be locked into one of these conformations depending on their specific structure. While many groups have researched these bridged nucleosides for the purpose of determining their binding affinity for antisense applications, we opted to look into the potential for biological activity within these conformationally-locked structures. A small library of 2′,4′- and 3′,4′-bridged nucleoside analogues was synthesized, including a novel 3′,4′-carbocyclic bridged system. The synthesized compounds were tested for antibacterial, antitumor, and antiviral activities, leading to the identification of nucleosides possessing such biological activities. To the best of our knowledge, these biologically active compounds represent the first example of 2′,4′-bridged nucleosides to demonstrate such properties. The most potent compound, nucleoside 33, exhibited significant antiviral activity against pseudoviruses SF162 (IC50 = 7.0 μM) and HxB2 (IC50 = 2.4 μM). These findings render bridged nucleosides as credible leads for drug discovery in the anti-HIV area of research.

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“…The gene encoding GR has been identified as essential in pathogenic bacteria such as Escherichia coli (E. coli) (Doublet et al, 1992), Streptococcus pneumoniae (S. pneumoniae) (de Dios et al, 2002), and Staphylococci (de Dios et al, 2002) justifying GR as a target for inhibitor design (Basarab et al, 2008;Breault et al, 2008;de Dios et al, 2002;Geng et al, 2008;Geng et al, 2009;Kim et al, 2000;Tanner and Miao, 1994;Tanner and Glavas, 1997). De Dios et al (2002) were the first to develop a group of potent small molecule inhibitors of GR from S. pneumoniae that were derivatives of (2R,4S)-4-substituted D-Glu (Fig.…”

Section: Introductionmentioning

confidence: 99%

A ligand-based approach for enhancing the pharmacokinetic profile of highly charged antibacterial agents

et al. 2011

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Glutamate racemase catalyses the interconversion of L-glutamate and D-glutamate making available D-glutamate which is essential for peptidoglycan biosynthesis. Inhibitors of this enzyme have exhibited antibacterial activity with the D-glutamate-analogues group of inhibitors being the most significant as it is the only group that has demonstrated efficacy in a murine thigh Streptococcus pneumoniae infection model. This group of inhibitors, however, showed a narrow antibacterial spectrum that could be due to poor lipophilicity and permeability properties. Here, we have adopted a computational ligand-based drug design approach to enhance the lipophilicity and, hence, the antibacterial spectrum of this group of inhibitors. By limiting the charged groups on our pharmacophore model and identifying key interactions for glutamate racemase binding and inhibition, we have successfully searched a compound database for compounds with both antibacterial activity and increased lipophilicity. However, our compounds appear less potent, likely due to decreased specificity. We also demonstrate that permeability and lipophilicity alone are not responsible for the narrow antibacterial spectrum observed in the D-glutamate analogue inhibitors.

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Exploring 9-benzyl purines as inhibitors of glutamate racemase (MurI) in Gram-positive bacteria

Cited by 21 publications

References 18 publications

New Frontiers in Druggability

New Frontiers in Druggability

Synthesis and biological evaluation of 2′,4′- and 3′,4′-bridged nucleoside analogues

A ligand-based approach for enhancing the pharmacokinetic profile of highly charged antibacterial agents

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