ABSTRACT
The bacterial deacetylase LpxC is a promising target for the development of novel antibiotics being selectively active against Gram-negative bacteria. In chiral pool syntheses starting from d- and l-ribose, a series regio- and stereoisomeric monohydroxytetrahydrofuran derivatives was synthesized and tested for LpxC inhibitory and antibacterial activities. Molecular docking studies were performed to rationalize the obtained structure-activity relationships. The (2S,3R,5R)-configured 3-hydroxytetrahydrofuran derivative ent-8 ((2S,3R,5R)-N,3-Dihydroxy-5-(4-{[4-(morpholinomethyl)phenyl]ethynyl}phenyl)tetrahydrofuran-2-carboxamide) was found to be the most potent LpxC inhibitor (Kiâ¯=â¯3.5⯵M) of the synthesized series of monohydroxytetrahydrofuran derivatives and to exhibit the highest antibacterial activity against E. coli BL21(DE3) and the D22 strain.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glycosides/chemistry , Glycosides/pharmacology , Amidohydrolases/drug effects , Amidohydrolases/metabolism , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Enzyme Inhibitors/chemical synthesis , Escherichia coli/drug effects , Escherichia coli/enzymology , Escherichia coli Infections/drug therapy , Glycosides/chemical synthesis , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/enzymology , Gram-Negative Bacterial Infections/drug therapy , Humans , Molecular Docking SimulationABSTRACT
LpxC inhibitors represent a promising class of novel antibiotics selectively combating Gram-negative bacteria. In chiral pool syntheses starting from D- and L-xylose, a series of four 2r,3c,4t-configured C-furanosidic LpxC inhibitors was obtained. The synthesized hydroxamic acids were tested for antibacterial and LpxC inhibitory activity, the acquired biological data were compared with those of previously synthesized C-furanosides, and molecular docking studies were performed to rationalize the observed structure-activity relationships. Additionally, bacterial uptake and susceptibility to efflux pump systems were investigated for the most promising stereoisomers.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/pharmacology , Enzyme Inhibitors/pharmacology , Molecular Docking Simulation , Xylose/pharmacology , Amidohydrolases/metabolism , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Molecular Structure , Structure-Activity Relationship , Xylose/chemical synthesis , Xylose/chemistryABSTRACT
Chalcogen bonding is the non-covalent interaction between Lewis acidic chalcogen substituents and Lewis bases. Herein, we present the first application of dicationic tellurium-based chalcogen bond donors in the nitro-Michael reaction between trans-ß-nitrostyrene and indoles. This also constitutes the first activation of nitro derivatives by chalcogen bonding (and halogen bonding). The catalysts showed rate accelerations of more than a factor of 300 compared to strongly Lewis acidic hydrogen bond donors. Several comparison experiments, titrations, and DFT calculations support a chalcogen-bonding-based mode of activation of ß-nitrostyrene.
ABSTRACT
Various neutral, mono- and dicationic halogen bond donors were screened for their ability to act as catalysts in a Nazarov cyclisation reaction. Using a highly preorganized dicationic catalyst with a noncoordinating counterion proved essential for high activity.
ABSTRACT
Inhibitors of the bacterial deacetylase LpxC are a promising class of novel antibiotics, being selectively active against Gram-negative bacteria. To improve the biological activity of reported C-furanosidic LpxC inhibitors, the stereochemistry at positionsâ 3 and 4 of the tetrahydrofuran ring was varied. In chiral pool syntheses starting from d-gulono-γ-lactone and d-ribose, a series of (3S,4R)-configured dihydroxytetrahydrofuran derivatives was obtained, of which the (2S,5S)-configured hydroxamic acid 15 ((2S,3S,4R,5S)-N,3,4-trihydroxy-5-(4-{[4-(morpholinomethyl)phenyl]ethynyl}phenyl)tetrahydrofuran-2-carboxamide) was found to be the most potent LpxC inhibitor (Ki =0.4â µm), exhibiting the highest antibacterial activity against E.â coli BL21 (DE3) and the D22 strain. Additionally, molecular docking studies were performed to rationalize the obtained structure-activity relationships.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Bacterial Proteins/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Furans/chemistry , Molecular Docking Simulation , Amidohydrolases/metabolism , Bacterial Proteins/metabolism , Binding Sites , Catalytic Domain , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Escherichia coli/drug effects , Escherichia coli/enzymology , Furans/metabolism , Furans/pharmacology , Hydroxamic Acids/chemistry , Microbial Sensitivity Tests , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The influence of charge on the performance of monocationic and dicationic triazol(ium)-based halogen bond donors was investigated. Next to the activity in a halide abstraction benchmark reaction, halogen bonding was also evaluated via X-ray structural analyses and isothermal titration calorimetry.
ABSTRACT
Hypervalent iodine(III) derivatives are known as versatile reagents in organic synthesis, but there is only one previous report on their use as Lewis acidic organocatalysts. Herein, we present first strong indications for the crucial role of halogen bonding in this kind of catalyses. To this end, the solvolysis of benzhydryl chloride and the Diels-Alder reaction of cyclopentadiene with methyl vinyl ketone served as benchmark reactions for halide abstraction and the activation of neutral compounds. Iodolium compounds (cyclic diaryl iodonium species) were used as activators or catalysts, and we were able to markedly reduce or completely switch off their activity by sterically blocking one or two of their electrophilic axes. Compared with previously established bidentate cationic halogen bond donors, the monodentate organoiodine derivatives used herein are at least similarly active (in the Diels-Alder reaction) or even decidedly more active (in benzhydryl chloride solvolysis).