D-cycloserine is an antibiotic which targets sequential bacterial cell wall peptidoglycan biosynthesis enzymes: alanine racemase and D-alanine:D-alanine ligase. By a combination of structural, ...chemical and mechanistic studies here we show that the inhibition of D-alanine:D-alanine ligase by the antibiotic D-cycloserine proceeds via a distinct phosphorylated form of the drug. This mechanistic insight reveals a bimodal mechanism of action for a single antibiotic on different enzyme targets and has significance for the design of future inhibitor molecules based on this chemical structure.
The Van enzymes are ATP-dependant ligases responsible for resistance to vancomycin in
Staphylococcus aureus and
Enteroccoccus species. The
de novo molecular design programme SPROUT was used in ...conjunction with the X-ray crystal structure of
Enterococcus faecium
d-alanyl-
d-lactate ligase (VanA) to design new putative inhibitors based on a hydroxyethylamine template. The two best ranked structures were selected and efficient syntheses developed. The inhibitory activities of these molecules were determined on
E. faecium VanA, and due to structural similarity and a common reaction mechanism, also on
d-Ala-
d-Ala ligase (DdlB) from
Escherichia coli. The phosphate group attached to the hydroxyl moiety of the hydroxyethylamine isostere within these systems is essential for their inhibitory activity against both VanA and DdlB.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
An improved, efficient, and simple method for the synthesis of nonsymmetrical diamides of fumaric acid is reported. Starting from commercially available substrates, maleic diamides are formed in two ...steps, and then isomerized in a focused microwave reactor in acetonitrile as the solvent in the presence of a catalytic amount of piperidine, giving the corresponding fumaramides in high yields and purity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
We describe the synthesis and biological activity of a new class of 1,3-diaryltriazenes, namely 4-nitro-substituted 1,3-diaryltriazenes. Structure–activity relationship analysis reveals that ...1,3-diaryltriazenes can be modified from inactive to highly cytotoxic compounds by the introduction of two nitro groups at the
para positions of benzene rings and two additional electron-withdrawing groups (bromo, chloro, trifluoromethyl or fluoro substituents) at their
ortho position. In order to increase the solubility of the modified compounds, we introduced various acyl groups to their triazene nitrogen. The results of LC-MS/MS analysis showed that
N-acyltriazenes can be considered as prodrugs of non-acylated triazenes. Selected 3-acetyl-1,3-
bis(2-chloro-4-nitrophenyl)-1-triazene (
8b) is highly cytotoxic against different tumor cell lines, including cisplatin-resistant laryngeal carcinoma cells. Notably, its antiproliferative activity is significantly higher against tumor cells than against normal cells. DNA binding analysis suggests that neither
8b nor its non-acylated derivative
8a bind into the minor groove of DNA. Instead,
8b induces reactive oxygen species that could provoke endoplasmic reticulum (ER
a
) stress finally leading to apoptosis. Our data suggest that 4-nitro-substituted 1,3-diaryltriazenes are a new class of anticancer molecules which preferentially target malignant cells and may serve as potential antitumor agents.
3-acetyl-1,3-
bis(2-chloro-4-nitrophenyl)-1-triazene (
8b).
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► Diaryltriazene
8b is highly cytotoxic against various tumor cells. ► Cytotoxic also to cisplatin-resistant tumor cells. ► Significantly less active against normal cells. ►
8b induces reactive oxygen species, endoplasmic reticulum stress and apoptosis. ► New compound
8b may serve as potential antitumor agent.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Despite efforts made in chemotherapeutic research in the past and present, Mycobacterium tuberculosis (M.tb), the etiological agent of tuberculosis, still causes more than a million deadly casualties ...each year, second only to HIV. The rapid generation and spread of drug resistant strains, a problem exacerbated by co-infection with HIV demands further efforts in the investigation of novel classes of anti-tubercular compounds. A library of eight substituted diazenecarboxamides, three carbamoyldiazenecarboxylates and four diazene-1,2-dicarboxamides was synthesized in a straightforward manner followed by a biological evaluation of the compounds. We observed minimal inhibitory concentrations below 10 μg/mL against the H37Rv lab strain of M.tb. Three compounds that showed a potency of 90% growth inhibition of M.tb at a concentration lower than 10 μg/mL were further evaluated and showed potency against other clinically relevant mycobacterial species such as Mycobacterium bovis, Mycobacterium avium and Mycobacterium ulcerans. The selected compounds were examined for acute cell toxicity on a murine macrophage like monocyte cell line J774 A.1 in which the cell viability was reduced by 50% at concentrations ranging from 7.4 μg/mL to 20.7 μg/mL. Neither of the three compounds showed signs of genotoxicity by VITOTOX or by Comet assay. The study was complemented by demonstration of the inhibition of intracellular replication of M.tb H37Rv inside J774 A.1 cells at 2 μg/mL concentration and the susceptibility of a MDR LAM-1 strain at concentrations between 5 and 1 μg/mL of the most active compound.
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•A library of diazene derivatives were synthesized in a straightforward manner.•The library was screened for potency against Mycobacterium tuberculosis.•Acute toxicity against murine J774 A.1 monocytes was studied.•Activity against MDR M.tb and intracellular replicating M.tb was confirmed.•No signs of genotoxicity were observed in vitro for the compounds.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A series of new inhibitors of the
d-alanine-
d-alanine ligase (Ddl) is presented. Thirteen diazenedicarboxamides were better inhibitors than
d-cycloserine, and some of them also possess antibacterial ...activity, which makes them a promising starting point for further development.
d-Alanine-
d-alanine ligase (Ddl) catalyzes the biosynthesis of an essential bacterial peptidoglycan precursor
d-alanyl-
d-alanine and it represents an important target for development of new antibacterial drugs. A series of semicarbazides, aminocarbonyldiazenecarboxylates, diazenedicarboxamides, and hydrazinedicarboxamides was synthesized and screened for inhibition of DdlB from
Escherichia coli. Compounds with good inhibitory activity were identified, enabling us to deduce initial structure–activity relationships. Thirteen diazenedicarboxamides were better inhibitors than
d-cycloserine and some of them also possess antibacterial activity, which makes them a promising starting point for further development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The ATP‐dependent UDP‐MurNAc‐tripeptide:D‐Ala‐D‐Ala ligase MurF catalyses the last step in the cytoplasmic phase of peptidoglycan biosynthesis, which is critical in the formation of the bacterial ...cell wall and in the recycling of peptidoglycan intermediates. In this study, the crystallization of MurF from the Gram‐negative pathogen Pseudomonas aeruginosa in the presence of its UDP‐MurNAc‐tripeptide substrate is reported. The crystals belonged to space group P212121, with unit‐cell parameters a = 57.81, b = 87.29, c = 92.61 Å, and data were collected to 1.92 Å resolution, allowing study of the enzyme in the substrate‐liganded form for the first time.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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