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1.
Antibiotics (Basel) ; 11(9)2022 Sep 02.
Article in English | MEDLINE | ID: mdl-36139968

ABSTRACT

New inhibitors of the bacterial transferase MraY from Aquifex aeolicus (MraYAA), based on the aminoribosyl uridine central core of known natural MraY inhibitors, have been designed to generate interaction of their oxadiazole linker with the key amino acids (H324 or H325) of the enzyme active site, as observed for the highly potent inhibitors carbacaprazamycin, muraymycin D2 and tunicamycin. A panel of ten compounds was synthetized notably thanks to a robust microwave-activated one-step sequence for the synthesis of the oxadiazole ring that involved the O-acylation of an amidoxime and subsequent cyclization. The synthetized compounds, with various hydrophobic substituents on the oxadiazole ring, were tested against the MraYAA transferase activity. Although with poor antibacterial activity, nine out of the ten compounds revealed the inhibition of the MraYAA activity in the range of 0.8 µM to 27.5 µM.

2.
Molecules ; 27(6)2022 Mar 08.
Article in English | MEDLINE | ID: mdl-35335131

ABSTRACT

New inhibitors of the bacterial tranferase MraY are described. Their structure is based on an aminoribosyl uridine scaffold, which is known to be important for the biological activity of natural MraY inhibitors. A decyl alkyl chain was introduced onto this scaffold through various linkers. The synthesized compounds were tested against the MraYAA transferase activity, and the most active compound with an original (S,S)-tartaric diamide linker inhibits MraY activity with an IC50 equal to 0.37 µM. Their antibacterial activity was also evaluated on a panel of Gram-positive and Gram-negative strains; however, the compounds showed no antibacterial activity. Docking and molecular dynamics studies revealed that this new linker established two stabilizing key interactions with N190 and H325, as observed for the highly potent inhibitors carbacaprazamycin, muraymycin D2 and tunicamycin.


Subject(s)
Diamide , Transferases , Bacterial Proteins/chemistry , Molecular Dynamics Simulation , Transferases/chemistry , Transferases (Other Substituted Phosphate Groups) , Uridine/chemistry , Uridine/pharmacology
3.
Org Biomol Chem ; 19(26): 5844-5866, 2021 07 14.
Article in English | MEDLINE | ID: mdl-34115086

ABSTRACT

The straightforward synthesis of aminoribosyl uridines substituted by a 5'-methylene-urea is described. Their convergent synthesis involves the urea formation from various activated amides and an azidoribosyl uridine substituted at the 5' position by an aminomethyl group. This common intermediate resulted from the diastereoselective glycosylation of a phthalimido uridine derivative with a ribosyl fluoride as a ribosyl donor. The inhibition of the MraY transferase activity by the synthetized 11 urea-containing inhibitors was evaluated and 10 compounds revealed MraY inhibition with IC50 ranging from 1.9 µM to 16.7 µM. Their antibacterial activity was also evaluated on a panel of Gram-positive and Gram-negative bacteria. Four compounds exhibited a good activity against Gram-positive bacterial pathogens with MIC ranging from 8 to 32 µg mL-1, including methicillin resistant Staphylococcus aureus (MRSA) and Enterococcus faecium. Interestingly, one compound also revealed antibacterial activity against Pseudomonas aeruginosa with MIC equal to 64 µg mL-1. Docking experiments predicted two modes of positioning of the active compounds urea chain in different hydrophobic areas (HS2 and HS4) within the MraY active site from Aquifex aeolicus. However, molecular dynamics simulations showed that the urea chain adopts a binding mode similar to that observed in structural model and targets the hydrophobic area HS2.


Subject(s)
Anti-Bacterial Agents
4.
Curr Med Chem ; 25(42): 6013-6029, 2018.
Article in English | MEDLINE | ID: mdl-29600753

ABSTRACT

The bacterial resistance to antibiotics constitutes more than ever a severe public health problem. The enzymes involved in bacterial peptidoglycan biosynthesis are pertinent targets for developing new antibiotics, notably the MraY transferase that is not targeted by any marketed drug. Many research groups are currently working on the study or the inhibition of this enzyme. After a concise overview of the role, mechanism and inhibition of MraY, the structure-activity relationships of 5'-triazole-containing aminoribosyluridine inhibitors, we previously synthetized, will be presented. The recently published MraY X-ray structures allowed us to achieve a molecular virtual high-throughput screening of commercial databases and our in-house library resulting in the identification of promising compounds for the further development of new antibiotics.


Subject(s)
Anti-Bacterial Agents/chemistry , Bacteria/metabolism , Bacterial Proteins/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Transferases/antagonists & inhibitors , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , Bacteria/enzymology , Bacterial Proteins/metabolism , Binding Sites , Drug Design , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Molecular Docking Simulation , Peptidoglycan/metabolism , Structure-Activity Relationship , Transferases/metabolism , Transferases (Other Substituted Phosphate Groups) , Triazoles/chemistry , Triazoles/metabolism
5.
Beilstein J Org Chem ; 13: 1533-1541, 2017.
Article in English | MEDLINE | ID: mdl-28845198

ABSTRACT

The 5'-alkynylation of uridine-derived aldehydes is described. The addition of alkynyl Grignard reagents on the carbonyl group is significantly influenced by the 2',3'-di-O-protecting groups (R1): O-alkyl groups led to modest diastereoselectivities (65:35) in favor of the 5'R-isomer, whereas O-silyl groups promoted higher diastereoselectivities (up to 99:1) in favor of the 5'S-isomer. A study related to this protecting group effect on the diastereoselectivity is reported.

6.
Org Biomol Chem ; 13(26): 7193-222, 2015 Jul 14.
Article in English | MEDLINE | ID: mdl-26008868

ABSTRACT

The straightforward synthesis of 5'-methylene-[1,4]-triazole-substituted aminoribosyl uridines is described. Two families of compounds were synthesized from a unique epoxide which was regioselectively opened by acetylide ions (for compounds II) or azide ions (for compounds III). Sequential diastereoselective glycosylation with a ribosyl fluoride derivative, Cu(i)-catalyzed azide-alkyne cycloaddition (CuAAC) with various complementary azide and alkyne partners afforded the targeted compounds after final deprotection. The biological activity of the 16 resulting compounds together with that of 14 previously reported compounds I, lacking the 5' methylene group, was evaluated on the MraY transferase activity. Out of the 30 tested compounds, 18 compounds revealed MraY inhibition with IC50 ranging from 15 to 150 µM. A molecular modeling study was performed to rationalize the observed structure-activity relationships (SAR), which allowed us to correlate the activity of the most potent compounds with an interaction involving Leu191 of MraYAA. The antibacterial activity was also evaluated and seven compounds exhibited a good activity against Gram-positive bacterial pathogens with MIC ranging from 8 to 32 µg mL(-1), including the methicillin resistant Staphylococcus aureus (MRSA).


Subject(s)
Bacterial Proteins/antagonists & inhibitors , Models, Molecular , Transferases/antagonists & inhibitors , Triazoles/chemistry , Uridine/chemistry , Uridine/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacillus subtilis/drug effects , Bacillus subtilis/enzymology , Bacterial Proteins/chemistry , Catalytic Domain , Chemistry Techniques, Synthetic , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Microbial Sensitivity Tests , Transferases/chemistry , Transferases (Other Substituted Phosphate Groups) , Uridine/chemical synthesis
7.
J Org Chem ; 79(16): 7758-65, 2014 Aug 15.
Article in English | MEDLINE | ID: mdl-25036849

ABSTRACT

A straightforward strategy for the synthesis of 5'-substituted-uridine derivatives is described. It relies on the introduction of various substituents at C-5' at the last step of the synthesis by regioselective nucleophilic opening of a unique epoxide that provides access to a small library of compounds. This epoxide results from the diastereoselective epoxidation, performed at a multigram scale, of a uridine-derived alkene. The configuration of the newly created 5' asymmetric center has been unambiguously assigned by X-ray diffraction analysis.


Subject(s)
Alkenes/chemistry , Uridine/analogs & derivatives , Uridine/chemistry , Epoxy Compounds/chemistry , Molecular Structure , Stereoisomerism , X-Ray Diffraction
8.
J Org Chem ; 78(20): 10088-105, 2013 Oct 18.
Article in English | MEDLINE | ID: mdl-24044436

ABSTRACT

A straightforward strategy for the synthesis of triazole-containing MraY inhibitors has been developed. It involves the sequential introduction of a terminal alkyne at the 5' position of an uridine derivative and O-glycosylation with a protected aminoribose leading to an elaborated alkyne scaffold. An efficient Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) allowed the introduction of chemical diversity toward a small library of inhibitors.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Bacterial Proteins/antagonists & inhibitors , Bacterial Proteins/chemistry , Copper/chemistry , Enzyme Inhibitors/chemical synthesis , Transferases/antagonists & inhibitors , Transferases/chemistry , Triazoles/chemical synthesis , Uridine/chemical synthesis , Alkynes/chemistry , Anti-Bacterial Agents/chemistry , Azides/chemistry , Catalysis , Cycloaddition Reaction , Drug Resistance, Bacterial , Enzyme Inhibitors/chemistry , Glycosylation , Transferases (Other Substituted Phosphate Groups) , Triazoles/chemistry , Uridine/chemistry
9.
J Org Chem ; 71(5): 2071-7, 2006 Mar 03.
Article in English | MEDLINE | ID: mdl-16496995

ABSTRACT

We report here two approaches for the preparation of new N-substituted beta-enamino ester piperidines featuring an exocyclic tetrasubstituted double bond, based either on the direct alkylation of piperidine beta-enamino esters bearing an exocyclic trisubstituted double bond or on the intramolecular cyclization of linear amino beta-keto esters. The target compounds were obtained as unusual (Z)-stereoisomers in high yields. The key role of ammonia as reagent, acting both as a nucleophile and a base, was underlined. The diastereoselective formation of the products was rationalized on the basis of an ammonia addition-syn elimination catalytic process.


Subject(s)
Ammonia/chemistry , Piperidines/chemical synthesis , Catalysis , Esters , Stereoisomerism
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