Abstract：
:Antibiotic resistance represents a worldwide concern, especially regarding the outbreak of methicillin-resistant Staphylococcus aureus, a common cause for serious skin and soft tissues infections. A major contributor to Staphylococcus aureus antibiotic resistance is the NorA efflux pump, which is able to extrude selected antibacterial drugs and biocides from the membrane, lowering their effective concentrations. Thus, the inhibition of NorA represents a promising and challenging strategy that would allow recycling of substrate antimicrobial agents. Among NorA inhibitors, the indole scaffold proved particularly effective and suitable for further optimization. In this study, some unexplored modifications on the indole scaffold are proposed. In particular, for the first time, substitutions at the C5 and N1 positions have been designed to give 48 compounds, which were synthesized and tested against norA-overexpressing S. aureus. Among them, 4 compounds have NorA IC50 values lower than 5.0 μM proving to be good efflux pump inhibitor (EPI) candidates. In addition, preliminary data on their ADME (absorption, distribution, metabolism, and excretion) profile is reported.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Lepri S,Buonerba F,Goracci L,Velilla I,Ruzziconi R,Schindler BD,Seo SM,Kaatz GW,Cruciani Gdoi
10.1021/acs.jmedchem.5b01219subject
Has Abstractpub_date
2016-02-11 00:00:00pages
867-91issue
3eissn
0022-2623issn
1520-4804journal_volume
59pub_type
杂志文章abstract：:Oligonucleotide-based therapeutics have made rapid progress in the clinic for treatment of a variety of disease indications. Unmodified oligonucleotides are polyanionic macromolecules with poor drug-like properties. Over the past two decades, medicinal chemists have identified a number of chemical modification and con...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
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abstract：:Dimeric DNA cross-linking compounds have emerged as important new antitumor agents. We report the synthesis and biochemical evaluation of a select set of dimeric mitomycins in which the two mitomycin units are tethered at either the mitomycin C(7) amino or the aziridine N(1a) positions. Significantly, mitomycin C (1) ...
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doi：10.1021/jm00343a008
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abstract：:Cholecystokinin (CCK) has been identified as a pronociceptive endogenous peptide which also possesses antiopioid actions. CCK may be upregulated in conditions of chronic pain or during sustained morphine administration resulting in attenuation of opioid-mediated pain relief. These complex interactions between opioids ...
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doi：10.1021/jm00396a008
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pub_type： 杂志文章
doi：10.1021/jm960213s
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abstract：:Most bromodomain inhibitors mimic the interactions of the natural acetylated lysine (KAc) histone substrate through key interactions with conserved asparagine and tyrosine residues within the binding pocket. Herein we report the optimization of a series of phenyl sulfonamides that exhibit a novel mode of binding to no...
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pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c00021
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pub_type： 杂志文章
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更新日期：2011-07-28 00:00:00
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更新日期：2006-06-29 00:00:00
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pub_type： 杂志文章
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