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Treatment of Ba[N(SiMe3)2]2(THF)2 with 2 equiv of dimethylaminotetrazole or diisopropylaminotetrazole and 1 equiv of 18-crown-6 afforded Ba[CN4(NMe2)]2(18-crown-6) (87%) and Ba[CN4(NiPr2)]2(18-crown-6) (79%) as colorless crystalline solids. Ba[CN4(NMe2)]2(18-crown-6) contains two 1,2-Β²-tetrazolato ligands and one Β618-crown-6 ligand. The molecular structure of Ba[CN4(NiPr2)]2(18-crown-6) is similar to that of Ba[CN4(NMe2)]2(18-crown-6), except that the tetrazolato ligands exhibit the isomeric 2,3-Β²-coordination mode and the tetrazolato ligand CN4 cores are bent significantly toward the 18-crown-6 ligands. Molecular orbital calculations were carried out on the model complexes Ba(azolate)2(18-crown-6) (azolate = 1,2-Β²-CHN4, 2,3-Β²-CHN4, and Β²-N5) and demonstrate that the ligand coordination modes are influenced by intramolecular interactions between filled nitrogen orbitals on the azolato ligands and empty C-H σ∗ orbitals on the 18-crown-6 ligands. [ABSTRACT FROM AUTHOR]

Studies pyrazolate-bridged digallium complexes containing bridging phenyl groups. Synthesis; Structure; Bridge-terminal exchange kinetics; Molecular orbital calculations.

Treatment of 3,5-diisopropyltriazole, 3,5-diphenyltriazole, 3,5-di-3-pyridyltriazole, phenyltetrazole, pyrrolidinyltetrazole, or tert-butyltetrazole with equimolar quantities of potassium hydride and 18-crown-6 in tetrahydrofuran at ambient temperature led to slow hydrogen evolution and formation of (3,5-diisopropyl-1,2,4-triazolato)(18-crown-6)potassium (88%), (3,5-diphenyl-1,2,4-triazolato)(tetrahydrofuran)(18-crown-6)potassium (87%), (3,5-di-3-pyridyl-1,2,4-triazolato)-(18-crown-6)potassium (81%), (phenyltetrazolato)(18-crown-6)potassium (94%), (pyrrolidinyltetrazolato)(18-crown- 6)potassium (90%), and (tert-butyltetrazolato)(18-crown-6)potassium (94%) as colorless crystalline solids. (1,2,4-Triazolato)(18-crown-6)potassium was isolated as a hemi-hydrate in 81% yield upon treatment of 1,2,4-triazole with potassium metal in tetrahydrofuran. The X-ray crystal structures of these new complexes were determined, and the solid-state structures consist of the nitrogen heterocycles bonded to the (18-crown-6)potassium cationic fragments with η²-bonding interactions. In addition, (3,5-diphenyl-1,2,4-triazolato)(tetrahydrofuran)(1 8-crown-6)-potassium has one coordinated tetrahydrofuran ligand on the same face as the 3,5-diphenyl-1,2,4-triazolato ligand, while (3,5-di-3-pyridyl-1,2,4-triazolato)(18-crown-6)potassium forms a polymeric solid through coordination of the distal 3-pyridyl nitrogen atoms to the potassium ion on the face opposite the 1,2,4-triazolato ligand. The solid-state structures of the new complexes show variable asymmetry in the potassium-nitrogen distances within the η²- interactions and also show variable bending of the heterocyclic C2N3 and CN4 cores toward the best plane of the 18-crown-6 ligand oxygen atoms. Molecular orbital and natural bond order calculations were carried out at the B3LYP/6-311G(d,p) level of theory on the model complex, (phenyltetrazolato)(18-crown-6)potassium, and demonstrate that the asymmetric potassium-nitrogen distances and bending of the CN4 core toward the 18-crown-6 ligand are due to hydrogen bond-like interactions between filled nitrogen-based orbitals and carbon-hydrogen f orbitals on the 18-crown-6 ligands. Calculations carried out on the model pentazolato complex (pentazolato)(18-crown-6)-potassium predict a structure in which the pentazolato ligand N5 core is bent by 45° toward the best plane of the 18-crown-6 oxygen atoms. Such bending is induced by the formation of intramolecular nitrogen-hydrogen-carbon hydrogen bonds. Examination of the solid-state structures of the new complexes reveals many intramolecular and intermolecular nitrogen-hydrogen distances of ≤3.0 Å which support the presence of nitrogen-hydrogen-carbon hydrogen bonds. [ABSTRACT FROM AUTHOR]

Abstract: Nitroimidazoles such as PA-824 and OPC-67683 are currently in clinical development as members of a promising new class of therapeutics for tuberculosis. While the antitubercular activity of these compounds is high, they both suffer from poor water solubility thus complicating development. We determined the single crystal X-ray structure of PA-824 and found a close packing of the nitroimidazoles facilitated by a pseudoaxial conformation of the p-trifluoromethoxybenzyl ether. To attempt to disrupt this tight packing by destabilizing the axial preference of this side chain, we prepared the two diastereomers of the 7-methyl-nitroimidazo-oxazine. Determination of the crystal structure of the 7-(S)-methyl derivative (5, cis) revealed that the benzylic side chain remained pseudoaxial while the 7-(R)-methyl derivative (6, trans) adopted the desired pseudoequatorial conformation. Both derivatives displayed similar activities against Mycobacterium tuberculosis, but neither showed improved aqueous solubility, suggesting that inherent lattice stability is not likely to be a major factor in limiting solubility. Conformational analysis revealed that all three compounds have similar energetically accessible conformations in solution. Additionally, these results suggest that the nitroreductase that initially recognizes PA-824 is somewhat insensitive to substitutions at the 7-position. [Copyright &y& Elsevier]

Abstract: With the aim of discovering potent and selective dengue NS3 protease inhibitors, we systematically synthesized and evaluated a series of tetrapeptide aldehydes based on lead aldehyde 1 (Bz-Nle-Lys-Arg-Arg-H, K i =5.8μM). In general, we observe that interactions of P2 side chain are more important than P1 followed by P3 and P4. Tripeptide and dipeptide aldehyde inhibitors also show low micromolar activity. Additionally, an effective non-basic, uncharged replacement of P1 Arg is identified. [Copyright &y& Elsevier]

The lipid A biosynthesis pathway is essential in Pseudomonas aeruginosa. LpxA and LpxD are the first and third enzymes in this pathway respectively, and are regarded as promising antibiotic targets. The unique structural similarities between these two enzymes make them suitable targets for dual-binding inhibitors, a characteristic that would decrease the likelihood of mutational resistance and increase cell-based activity. We report the discovery of multiple small molecule ligands that bind to P. aeruginosa LpxA and LpxD, including dual-binding ligands. Binding poses were determined for select compounds by X-ray crystallography. The new structures reveal a previously uncharacterized magnesium ion residing at the core of the LpxD trimer. In addition, ligand binding in the LpxD active site resulted in conformational changes in the distal C-terminal helix-bundle, which forms extensive contacts with acyl carrier protein (ACP) during catalysis. These ligand-dependent conformational changes suggest a potential allosteric influence of reaction intermediates on ACP binding, and vice versa. Taken together, the novel small molecule ligands and their crystal structures provide new chemical scaffolds for ligand discovery targeting lipid A biosynthesis, while revealing structural features of interest for future investigation of LpxD function. [ABSTRACT FROM AUTHOR]