Increasing antibiotic resistance makes the identification of new antibacterial principles an urgent task. The thioredoxin system including thioredoxin reductase (TrxR), thioredoxin (Trx), and NADPH plays critical roles in cellular DNA synthesis and defense against oxidative stress. Notably, TrxR is very different in structure and mechanism in mammals and bacteria. Ebselen [2-phenyl-1,2 benzisoselenazol-3(2H)-one], a well-known antioxidant and a substrate for mammalian TrxR and Trx, is rapidly bacteriocidal for methicillin-resistant Staphylococcus aureus by an unknown mechanism. We have discovered that ebselen is a competitive inhibitor of Escherichia coli TrxR with a Ki of 0.52 ± 0.13 μM, through reaction with the active site dithiol of the enzyme. Bacteria lacking glutathione (GSH) and glutaredoxin, in which TrxR and Trx are essential for DNA synthesis, were particularly sensitive to ebselen. In growth-inhibited E. coli strains, Trx1 and Trx2 were oxidized, demonstrating that electron transfer via thioredoxin was blocked. Ebselen and its sulfur analog ebsulfur were bactericidal for GSH-negative pathogens. Ebsulfur inhibited a clinically isolated Helicobacter pylori strain with a minimum inhibitory concentration value as low as 0.39 μg/ml. These results demonstrate that bacterial Trx and TrxR are viable antibacterial drug targets using benzisoselenazol and benzisothiazol derivates.
A series of novel low-valent organotellurium compounds incorporating [2-[1-(3,5-dimethylphenyl)-2-naphthyl]-4,5-dihydro-4,4-dimethyloxazole] (1) stabilized by Te‚‚‚N nonbonded interactions have been synthesized. The synthesis has been achieved by the ortholithium route. The lithium arenetellurolate 3 was obtained by direct metalation of 1 with 1.6 M of n-BuLi in hexane followed by the insertion of tellurium into the Li-C bond. Oxidation of 3 then afforded the desired ditelluride 4. The reaction of 4 with a stoichiometric amount of sulfuryl chloride yielded stable tellurenyl(II) chloride 5, whereas the addition of an excess sulfuryl chloride led to the formation of tellurium(IV) trichloride 6. The stable bromo compound 7 was obtained by the controlled bromination of 4 with bromine. No tellurium tribromide formation was observed when the ditelluride was treated with an excess of bromine. Compound 4 underwent facile reaction with a stoichiometric amount of iodine to give a stable mono iodo compound (8). The phenyltelluride derivative 9 was obtained by the treatment of lithiated product 2 with PhTeBr at low temperature. Attempts to synthesize the symmetrical telluride of the type R 2 Te (10) by the reaction of 2 with Te(dtc) 2 (dtc ) diethyldithiocarbamate) or TeI 2 were unsuccessful. All compounds were characterized by elemental analysis, multinuclear ( 1 H, 13 C, 125 Te) NMR, and mass spectrometry techniques. The presence of strong Te‚‚‚N intramolecular nonbonded interactions in all the compounds was confirmed by single-crystal X-ray crystallographic studies.
The reaction of [2-(2-phenyl-5,6-dihydro-4H-1,3-oxazinyl)]lithium (13), containing a six-membered oxazine ring, with elemental selenium gave lithium aryldiselenolate (14) as the major reaction intermediate along with other polyselenolates (15 and 16), whereas [2-(4,4-dimethyl-2-phenyloxazolinyl]lithium (21), containing a five-membered oxazoline ring, on reaction with selenium gave only lithium arlyselenolate 22 under similar conditions. The unusual selenation reaction of aryllithium 13 has been studied by ES-MS spectrometry. The oxidative workup of in situ-generated lithium arylpolyselenolates (14−16) afforded a mixture of diorganopolyselenides (10, 11, 17, and 18), from which diorganotriselenide 11 was obtained as the major product, whereas lithium arylselenolate 22 gave only diselenide 6 on oxidation. Equimolar reactions of diorganotriselenide 11 with sulfuryl chloride and benzenethiol give the novel selenium halide [RSeSeCl (24)] and seleniumselenenyl sulfide (28), respectively. However, the reaction of triselenide 11 with an excess amount of halogenating reagents afforded selenenyl halides [RSeX; X = Cl (25), Br (26), I (27)]. The reaction of lithium arylpolyselenolates (14−16) with benzyl chloride gave a mixture of diselenide (10), unsymmetrical diselenide (31), benzyl selenide (32), and dibenzyl diselenide (33). The reaction of 14−16 with α,α‘-dibromo-ortho-xylene gave the 10-membered diselenocine (34) and 26. GPx-like activities of diselenide 10 and triselenide 11 have been evaluated by using both benzenethiol and coupled reductase assay methods. Triselenide 11 shows much better GPx-like activity than diselenide 10. Crystal structures of organoselenium compounds (11, 25−27, 29, 32, and 34) were determined by single X-ray crystallography to study the ring size effect of the oxazine ring on Se···N intramolecular interactions.
Synthesis of seven complexes containing oxazoline ([(L(1))(2)V=O] (4), [(L(1))(2)MoO(2)] (5), [(L(1))(2)UO(2)] (6); HL(1) (1) [HL(1) = 2-(4',4'-dimethyl-3'-4'-dihydroxazol-2'-yl)phenol]), chiral oxazoline ([(L(2))(2)UO(2)] (7); HL(2) (2) [HL(2) = (4'R)-2-(4'-ethyl-3'4'-dihyroxazol-2'-yl)phenol]), and oxazine ([(L(3))(2)V=O] (8), [(L(3))(2)Mn(CH(3)COO(-))] (9), [(L(3))(2)Co] (10); HL(3) (3) [HL(3) = 2-(5,6-dihydro-4H-1,3-oxazolinyl)phenol]) and their characterization by various techniques such as UV-vis, IR, and EPR spectroscopy, mass spectrometry, cyclic voltammetry, and elemental analysis are reported. The novel oxazine (3) and complexes 4, 5, 8 and 9 were also characterized by X-ray crystallography. Oxazine 3 crystallizes in the monoclinic system with the P2(1)/n space group, complexes 4 and 9 crystallize in the monoclinic system with the P2(1)/c space group, and complexes 5 and 8 crystallize in the orthorhombic system with the C222(1) space group and the P2(1)2(1)2(1) chiral space group, respectively. The representative synthetic procedure involves the reaction of metal acetate or acetylacetonate derivatives with corresponding ligand in ethanol. Addition of Mn(OAc)(2).4H(2)O to an ethanol solution of 3 gave the unexpected complex Mn(L(3))(2).(CH(3)COO(-)) (9) where the acetate group is coordinated with the metal center in a bidentate fashion. The catalytic activity of complexes 4-9 for oxidation of styrene with tert-butyl hydroperoxide was tested. In all cases, benzaldehyde formed exclusively as the oxidation product.
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