Inhibition of the ANT(2″)-Ia resistance enzyme and rescue of aminoglycoside antibiotic activity by synthetic α-hydroxytropolones

Hirsch, Danielle R.; Cox, Georgina; D’Erasmo, Michael P.; Shakya, Tushar; Meck, Christine; Mohd, Noushad; Wright, Gerard D.; Murelli, Ryan P.

doi:10.1016/j.bmcl.2014.09.037

Cited by 45 publications

(46 citation statements)

References 48 publications

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“…7 We have been leveraging an oxidopyrylium cycloaddition/ring-opening strategy toward their synthesis and usage in a number of different medicinal chemistry studies such as the development of antivirals against HIV, 8 Hepatitis B, 9 and herpes simplex virus, 10 and as inhibitors of the aminoglycoside resistance enzyme ANT(2”)-Ia. 11 To date, our method has relied upon a final demethylation using refluxing HBr/AcOH conditions. 12 …”

Section: Resultsmentioning

confidence: 99%

Discovery and Development of a Three-Component Oxidopyrylium [5 + 2] Cycloaddition

et al. 2016

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α-Hydroxy-γ-pyrone-based oxidopyrylium cycloaddition reactions are useful methods for accessing highly diverse range of oxabicyclo[3.2.1]octane products. Intermolecular variants of the reaction require the formation of a methyl triflate-based pre-ylide salt that upon treatment to base in the presence of alkenes or alkynes leads to α-methoxyenone-containing bicyclic product. Herein, we describe our discovery that the use of ethanol-stabilized chloroform as solvent leads to the generation of α-ethoxyenone-containing bicyclic byproducts. This 3-component process was further optimized by gently heating a mixture of a purified version of the oxidopyrylium dimer in the presence of the alcohol prior to addition of the dipolarophile. Using this convenient procedure, several new oxidopyrylium cycloaddition products can be generated in moderate yields. We also highlight the method in a tandem ring-opening/debenzylation method for the generation of α-hydroxytropolones.

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Section: Resultsmentioning

confidence: 99%

Discovery and Development of a Three-Component Oxidopyrylium [5 + 2] Cycloaddition

et al. 2016

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“…Three αHTs, numbered 106, 111, and 115, were synthesized from kojic acid as previously described (Hirsch et al, 2014; Meck et al, 2012; Williams et al, 2013). The chemical structure of each compound is detailed in Fig.…”

Section: Methodsmentioning

confidence: 99%

Broad anti-herpesviral activity of α-hydroxytropolones

Dehghanpir

Birkenheuer

Yang

et al. 2018

Veterinary Microbiology

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Herpesviruses are ubiquitous in animals and cause economic losses concomitant with many diseases. Most of the domestic animal herpesviruses are within the subfamily Alphaherpesvirinae, which includes human herpes simplex virus 1 (HSV-1). Suppression of HSV-1 replication has been reported with α-hydroxytropolones (αHTs), aromatic ring compounds that have broad bioactivity due to potent chelating activity. It is postulated that αHTs inhibit enzymes within the nucleotidyltransferase superfamily (NTS). These enzymes require divalent cations for nucleic acid cleavage activity. Potential targets include the nuclease component of the herpesvirus terminase (pUL15C), a highly conserved NTS-like enzyme that cleaves viral DNA into genomic lengths prior to packaging into capsids. Inhibition of pUL15C activity in biochemical assays by various αHTs previously revealed a spectrum of potencies. Interestingly, the most potent anti-pUL15C αHT inhibited HSV-1 replication to a limited extent in cell culture. The aim of this study was to evaluate three different αHT molecules with varying biochemical anti-pUL15C activity for a capacity to inhibit replication of veterinary herpesviruses (BoHV-1, EHV-1, and FHV-1) and HSV-1. Given the known discordant potencies between anti-pUL15C and HSV-1 replication inhibition, a second objective was to elucidate the mechanism of action of these compounds. The results show that αHTs broadly inhibit herpesviruses, with similar inhibitory effect against HSV-1, BoHV-1, EHV-1, and FHV-1. Based on immunoblotting, Southern blotting, and real-time qPCR, the compounds were found to specifically inhibit viral DNA replication. Thus, αHTs represent a new class of broadly active anti-herpesviral compounds with potential veterinary applications.

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“…Compounds 95 to 104 were synthesized from manicol as previously described (39) and exceeded 95% purity, as determined by liquid chromatography-mass spectrometry (LCMS). Compounds 106 to 117, 119, 120, 143 to 147, and 173 were synthesized in 5 to 7 steps from kojic acid as previously described (49)(50)(51). Synthetic ␣-hydroxytropolones were pure as determined by 1 H nuclear magnetic resonance (NMR) analysis, as reported previously, and a spectrum of compound 118 is provided in Fig.…”

Section: Methodsmentioning

confidence: 99%

Synthetic α-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses

Ireland

Tavis

D’Erasmo

et al. 2016

Antimicrob Agents Chemother

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cHerpes simplex virus 1 (HSV-1) and HSV-2 remain major human pathogens despite the development of anti-HSV therapeutics as some of the first antiviral drugs. Current therapies are incompletely effective and frequently drive the evolution of drug-resistant mutants. We recently determined that certain natural troponoid compounds such as ␤-thujaplicinol readily suppress HSV-1 and HSV-2 replication. Here, we screened 26 synthetic ␣-hydroxytropolones with the goals of determining a preliminary structure-activity relationship for the ␣-hydroxytropolone pharmacophore and providing a starting point for future optimization studies. Twenty-five compounds inhibited HSV-1 and HSV-2 replication at 50 M, and 10 compounds inhibited HSV-1 and HSV-2 at 5 M, with similar inhibition patterns and potencies against both viruses being observed. The two most powerful inhibitors shared a common biphenyl side chain, were capable of inhibiting HSV-1 and HSV-2 with a 50% effective concentration (EC 50 ) of 81 to 210 nM, and also strongly inhibited acyclovir-resistant mutants. Moderate to low cytotoxicity was observed for all compounds (50% cytotoxic concentration [CC 50 ] of 50 to >100 M). Therapeutic indexes ranged from >170 to >1,200. These data indicate that troponoids and specifically ␣-hydroxytropolones are a promising lead scaffold for development as anti-HSV drugs provided that toxicity can be further minimized. Troponoid drugs are envisioned to be employed alone or in combination with existing nucleos(t)ide analogs to suppress HSV replication far enough to prevent viral shedding and to limit the development of or treat nucleos(t)ide analog-resistant mutants.

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Inhibition of the ANT(2″)-Ia resistance enzyme and rescue of aminoglycoside antibiotic activity by synthetic α-hydroxytropolones

Cited by 45 publications

References 48 publications

Discovery and Development of a Three-Component Oxidopyrylium [5 + 2] Cycloaddition

Discovery and Development of a Three-Component Oxidopyrylium [5 + 2] Cycloaddition

Broad anti-herpesviral activity of α-hydroxytropolones

Synthetic α-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses

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