5 research outputs found
Synthesis, anticancer and antiviral activities of novel thiopyrano[2,3-<i>d</i>]thiazole-6-carbaldehydes
<p>Novel rel-(6R,7R)-2-oxo-7-phenyl-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d]thiazole-6-carbaldehydes were synthesized via regio- and diastereoselective hetero-Diels-Alder reaction of 5-arylidene-4-thioxo-2-thiazolidinones with acrolein. The synthesized compounds were evaluated for anticancer and antiviral activities by the National Institutes of Health (NIH) following US NCI and AACF protocols. Anticancer activity screening on NCI60 cell lines allowed identification of 7-phenyl-2-oxo-7-phenyl-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d]thiazole-6-carbaldehyde <b>3a</b> with the highest level of antimitotic activity against leukemia with mean GI<sub>50</sub>/TGI values 1.26/25.22 μM. The screening of antiviral activity lead to identification of 7-(4-methoxyphenyl)-2-oxo-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d]thiazole-6-carbaldehyde <b>3b</b> with a promising influence on EBV virus (EC<sub>50</sub> = 0.07 μM, SI = 3279) and moderate effect on Herpes simplex virus type 1 and Varicella zoster virus and 7-[4-(benzyloxy)phenyl]-2-oxo-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d][1,3]thiazole-6-carbaldehyde <b>3e</b> with a promising influence on Hepatitis C virus (EC<sub>50</sub> = 12.6 μM, SI = 43.1).</p
Potentiating Activity of GmhA Inhibitors on Gram-Negative Bacteria
Inhibition of the biosynthesis of bacterial heptoses
opens novel
perspectives for antimicrobial therapies. The enzyme GmhA responsible
for the first committed biosynthetic step catalyzes the conversion
of sedoheptulose 7-phosphate into d-glycero-d-manno-heptose 7-phosphate and harbors
a Zn2+ ion in the active site. A series of phosphoryl-
and phosphonyl-substituted derivatives featuring a hydroxamate moiety
were designed and prepared from suitably protected ribose or hexose
derivatives. High-resolution crystal structures of GmhA complexed
to two N-formyl hydroxamate inhibitors confirmed
the binding interactions to a central Zn2+ ion coordination
site. Some of these compounds were found to be nanomolar inhibitors
of GmhA. While devoid of HepG2 cytotoxicity and antibacterial activity
of their own, they demonstrated in vitro lipopolysaccharide heptosylation
inhibition in Enterobacteriaceae as
well as the potentiation of erythromycin and rifampicin in a wild-type Escherichia coli strain. These inhibitors pave the
way for a novel treatment of Gram-negative infections
Potentiating Activity of GmhA Inhibitors on Gram-Negative Bacteria
Inhibition of the biosynthesis of bacterial heptoses
opens novel
perspectives for antimicrobial therapies. The enzyme GmhA responsible
for the first committed biosynthetic step catalyzes the conversion
of sedoheptulose 7-phosphate into d-glycero-d-manno-heptose 7-phosphate and harbors
a Zn2+ ion in the active site. A series of phosphoryl-
and phosphonyl-substituted derivatives featuring a hydroxamate moiety
were designed and prepared from suitably protected ribose or hexose
derivatives. High-resolution crystal structures of GmhA complexed
to two N-formyl hydroxamate inhibitors confirmed
the binding interactions to a central Zn2+ ion coordination
site. Some of these compounds were found to be nanomolar inhibitors
of GmhA. While devoid of HepG2 cytotoxicity and antibacterial activity
of their own, they demonstrated in vitro lipopolysaccharide heptosylation
inhibition in Enterobacteriaceae as
well as the potentiation of erythromycin and rifampicin in a wild-type Escherichia coli strain. These inhibitors pave the
way for a novel treatment of Gram-negative infections
Novel HldE‑K Inhibitors Leading to Attenuated Gram Negative Bacterial Virulence
We report here the optimization of an HldE kinase inhibitor
to
low nanomolar potency, which resulted in the identification of the
first reported compounds active on selected <i>E. coli</i> strains. One of the most interesting candidates, compound <b>86</b>, was shown to inhibit specifically bacterial LPS heptosylation
on efflux pump deleted <i>E. coli</i> strains. This compound
did not interfere with <i>E. coli</i> bacterial growth (MIC
> 32 μg/mL) but sensitized this pathogen to hydrophobic antibiotics
like macrolides normally inactive on Gram-negative bacteria. In addition, <b>86</b> could sensitize <i>E. coli</i> to serum complement
killing. These results demonstrate that HldE kinase is a suitable
target for drug discovery. They also pave the way toward novel possibilities
of treating or preventing bloodstream infections caused by pathogenic
Gram negative bacteria by inhibiting specific virulence factors
Structural–Functional Studies of <i>Burkholderia cenocepacia</i> d‑Glycero-β‑d‑manno-heptose 7‑Phosphate Kinase (HldA) and Characterization of Inhibitors with Antibiotic Adjuvant and Antivirulence Properties
As an essential constituent of the outer membrane of
Gram-negative bacteria, lipopolysaccharide contributes significantly
to virulence and antibiotic resistance. The lipopolysaccharide biosynthetic
pathway therefore serves as a promising therapeutic target for antivirulence
drugs and antibiotic adjuvants. Here we report the structural–functional
studies of d-glycero-β-d-manno-heptose 7-phosphate
kinase (HldA), an absolutely conserved enzyme in this pathway, from <i>Burkholderia cenocepacia</i>. HldA is structurally similar to
members of the PfkB carbohydrate kinase family and appears to catalyze
heptose phosphorylation via an in-line mechanism mediated mainly by
a conserved aspartate, Asp270. Moreover, we report the structures
of HldA in complex with two potent inhibitors in which both inhibitors
adopt a folded conformation and occupy the nucleotide-binding sites.
Together, these results provide important insight into the mechanism
of HldA-catalyzed heptose phosphorylation and necessary information
for further development of HldA inhibitors