Precursor Engineering for the Synthesis of Mixed Anionic Metal (Cu, Mn) Chalcogenide Nanomaterials via Solvent-Less Synthesis.

Metal-organic ligands with mixed chalcogenides are potential compounds for the preparation of mixed anionic metal chalcogenide alloys. However, only a few of such ligands are known, and their complexes are not well explored. We have prepared homo- and hetero-dichalcogenoimidodiphosphinate [(EE'PiPr2NH)] (E, E' = Se, Se; S, S; S, Se) complexes of manganese and copper through metathetical reactions. The X-ray single crystal structure of [Mn{(SePiPr2)2N}2] 1 revealed a triclinic crystal system, with a MnSe4 core unit, whereas the crystal structure determination of [Mn{(SPiPr2)(SePiPr2)N}2] 2 indicated a triclinic crystal system with a Mn(S/Se)2 unit. Both metal centers are tetrahedral, with two deprotonated bidentate ligands forming the coordination sphere. The free ligand was found to exhibit a gauche configuration in the solid state. The energies of the various rotamers of dithio-analogue were studied by DFT calculations. The decomposition behavior of complexes with homo- and heterochalcogenides was investigated, and the complexes were employed as single-source precursors to generate manganese and copper chalcogenides through solvent-less melt reactions between 500 and 550 °C. The deposited powders were characterized by powder X-ray diffraction (p-XRD), scanning electron microscopy (SEM), energy dispersive analysis of X-ray (EDAX), transmission electron microscopy (TEM), and elemental mapping. MnS, MnSe2, and MnSSe phases were obtained from the decomposition of respective manganese complexes. In contrast, the decomposition of copper-based complexes yielded Cu2-xSe and the sulfur-doped Cu3Se2 phase from seleno- and mixed thio/seleno-complexes of Cu, respectively. The morphology ranged from random sheet-like structures to agglomerated platelets, while the selected area electron diffraction (SAED) revealed the crystalline nature of the materials. Depending on the nature of the complex and the temperature, different amounts of phosphorus were present as an impurity in the synthesized products.

Evidence for Inhibition of Topoisomerase 1A by Gold(III) Macrocycles and Chelates Targeting Mycobacterium tuberculosis and Mycobacterium abscessus.

Mycobacterium tuberculosis and the fast-growing species Mycobacterium abscessus are two important human pathogens causing persistent pulmonary infections that are difficult to cure and require long treatment times. The emergence of drug-resistant M. tuberculosis strains and the high level of intrinsic resistance of M. abscessus call for novel drug scaffolds that effectively target both pathogens. In this study, we evaluated the activity of bis(pyrrolide-imine) gold(III) macrocycles and chelates, originally designed as DNA intercalators capable of targeting human topoisomerase types I and II (Topo1 and Topo2), against M. abscessus and M. tuberculosis We identified a total of 5 noncytotoxic compounds active against both mycobacterial pathogens under replicating in vitro conditions. We chose one of these hits, compound 14, for detailed analysis due to its potent bactericidal mode of inhibition and scalable synthesis. The clinical relevance of this compound was demonstrated by its ability to inhibit a panel of diverse M. tuberculosis and M. abscessus clinical isolates. Prompted by previous data suggesting that compound 14 may target topoisomerase/gyrase enzymes, we demonstrated that it lacked cross-resistance with fluoroquinolones, which target the M. tuberculosis gyrase. In vitro enzyme assays confirmed the potent activity of compound 14 against bacterial topoisomerase 1A (Topo1) enzymes but not gyrase. Novel scaffolds like compound 14 with potent, selective bactericidal activity against M. tuberculosis and M. abscessus that act on validated but underexploited targets like Topo1 represent a promising starting point for the development of novel therapeutics for infections by pathogenic mycobacteria.

Gold(III) macrocycles: nucleotide-specific unconventional catalytic inhibitors of human topoisomerase I.

Topoisomerase IB (Top1) is a key eukaryotic nuclear enzyme that regulates the topology of DNA during replication and gene transcription. Anticancer drugs that block Top1 are either well-characterized interfacial poisons or lesser-known catalytic inhibitor compounds. Here we describe a new class of cytotoxic redox-stable cationic Au(3+) macrocycles which, through hierarchical cluster analysis of cytotoxicity data for the lead compound, 3, were identified as either poisons or inhibitors of Top1. Two pivotal enzyme inhibition assays prove that the compounds are true catalytic inhibitors of Top1. Inhibition of human topoisomerase IIα (Top2α) by 3 was 2 orders of magnitude weaker than its inhibition of Top1, confirming that 3 is a type I-specific catalytic inhibitor. Importantly, Au(3+) is essential for both DNA intercalation and enzyme inhibition. Macromolecular simulations show that 3 intercalates directly at the 5'-TA-3' dinucleotide sequence targeted by Top1 via crucial electrostatic interactions, which include π-π stacking and an Au···O contact involving a thymine carbonyl group, resolving the ambiguity of conventional (drug binds protein) vs unconventional (drug binds substrate) catalytic inhibition of the enzyme. Surface plasmon resonance studies confirm the molecular mechanism of action elucidated by the simulations.

Chiral Au(III) chelates exhibit unique NCI-60 cytotoxicity profiles and interactions with human serum albumin.

Au(III) bis(pyrrolide-imine) chelates are emerging as a class of versatile, efficacious metallodrug candidates. Here, we synthesised two enantiopure chiral ligands H2L1 and H2L2 (tetradentate cyclohexane-1,2-diamine-bridged bis(pyrrole-imine) derivatives). Metallation of the ligands with Au(III) afforded the chiral cationic complexes AuL1 and AuL2. The in vitro cytotoxicities of AuL1 and AuL2 determined in the NCI-60 single-dose drug screen were 56.5% and 89.1%, respectively. AuL1 was subsequently selected for a five-dose NCI-60 screen, attaining GI50, IC50, and LC50 values of 4.7, 9.3 and 39.8 µM, respectively. Hierarchical cluster analysis of the NCI-60 data indicated that the profile for AuL1 was similar to that of vinblastine sulfate, a microtubule-targeting vinca alkaloid. Reactions of AuL1 with glutathione (GSH) in vitro confirmed its susceptibility to reduction, Au(III) → Au(I), by intracellular thiols. Because human serum albumin (HSA) is responsible for transporting clinically deployed and investigational drugs, we studied the uptake of AuL1 and AuL2 by HSA to delineate how chirality impacts their protein-binding affinity. Steady-state fluorescence quenching data acquired on the native protein and data from site-specific probes showed that the compounds bind at sites close enough to Trp-214 (subdomain IIA) of HSA to quench the fluorophore. The bimolecular quenching rate constants, Kq, were ca. 102 times higher than the maximum diffusion-controlled collision constant of a biomolecule in water (1010 M-1 s-1), confirming that static fluorescence quenching was the dominant mechanism. The Stern-Volmer constants, KSV, were ∼104 M-1 at 37 °C, while the affinity constants, Ka (37 °C), measured ∼2.1 × 104 M-1 (AuL1) and ∼1.2 × 104 M-1 (AuL2) for enthalpy-driven ligand uptake targeting Sudlow's site I. Although far- and near-UV CD spectroscopy indicated that both complexes minimally perturb the secondary and tertiary structure of HSA, substantial shifts in the CD spectra were recorded for both protein-bound ligands. This study highlights the role of chirality in determining the cytotoxicity profiles and protein binding behaviour of enantiomeric Au(III) chelates.

Biodistribution (as determined by the radiolabelled equivalent) of a gold(III) bis(pyrrolide-imine) Schiff base complex: a potential chemotherapeutic.

The biodistribution of an N2 N2 ' tetradentate gold(III) chelate, which is known to be cytotoxic towards a range of human cancer cell lines, was determined by a radiolabelled equivalent of the compound. The (198) Au-labelled gold(III) chelate of a bis(pyrrolide-imine) Schiff base ligand with a three-carbon di(azomethine) linkage was successfully synthesised with a high radiochemical yield of 73% and radiochemical purity of >95%. The high energy γ-ray emitted by the (198) Au nucleus was used to follow the biodistribution of the compound in vivo in six male Sprague Dawley rats on a gamma camera. The log Po/w value of the (nat) Au analogue, -1.92(2), showed that the compound is hydrophilic and therefore likely to largely remain in the blood pool. This was confirmed by the biodistribution study, which showed 21% of the injected dose (ID) remained in the blood pool 4.5 h after injection. This decreased to 10.8% over a 24-h period. The activity measured in the lungs, 1.48%ID/g, remained relatively constant over a 24-h period suggesting that the complex had accumulated in the lungs in the form of particulates, and could not be cleared by the test subjects. The t½ for the heart and lungs was greater than 24 h. Excretion of the test compound is seemingly via the kidneys, but is slow with approximately 30% of the ID excreted within 24 h.

(E)-2,3-Bis[(E)-benzyl-idene-amino]-but-2-enedinitrile.

The asymmetric unit of the title compound, C(18)H(12)N(4), consists of a half-mol-ecule, where the two halves of the mol-ecule are related by inversion symmetry. The mol-ecule is effectively planar, with the largest deviation from the 22-atom mean plane, measuring 0.024 (2) Å, exhibited by the ortho-C atom of the phenyl ring. The crystal structure exhibits π-stacking, with an inter-planar spacing of 3.431 (3) Å.

6-Amino-1,3-dimethyl-5-[(E)-2-(methyl-sulfan-yl)benzyl-idene-amino]-pyrimidine-2,4(1H,3H)-dione-1,3,7,9-tetra-methyl-pyrimido[5,4-g]pteridine-2,4,6,8-tetrone (1/1).

In the title co-crystal, C(12)H(12)N(6)O(4)·C(14)H(16)N(4)O(2)S, both mol-ecules are essentially planar [maximum deviations = 0.129 (1) and 0.097 (1) Å, respectively]. The tricyclic and Schiff base mol-ecules are alternately stacked along the a axis and are linked by π-π inter-actions with centroid-centroid distances of 3.5170 (16) and 3.6576 (17) Å. An intra-molecular C-H⋯O hydrogen bond and a C-H⋯S contact occur in the Schiff base molecule. In the crystal, N-H⋯O, N-H⋯N and C-H⋯O hydrogen bonds lead to the formation of a three-dimensional network.

N-[(E)-Thio-phen-2-yl-methyl-idene]-1,3-benzothia-zol-2-amine.

In the title thio-phene-derived Schiff base compound, C(12)H(8)N(2)S(2), the thio-phene ring is slighty rotated from the benzothia-zole group mean plane, giving a dihedral angle of 12.87 (6)°. The largest displacement of an atom in the mol-ecule from the nine-atom mean plane defined by the non-H atoms of the benzothia-zole ring system is 0.572 (1) Å, exhibited by the C atom at the 3-position of the thio-phene ring. In the crystal, weak C-H⋯S hydrogen bonds involving the thio-phene group S atom and the 4-position thio-phene C-H group of a symmetry-related mol-ecule lead to an infinite one-dimensional chain colinear with the c axis. The structure is further stabilized by π-π inter-actions; the distance between the thia-zole ring centroid and the centroid of an adjacent benzene ring is 3.686 (1) Å. The crystal studied was an inversion twin with the ratio of components 0.73 (3):0.27 (3).

N,N-Bis(pyridin-2-ylmeth-yl)cyclo-hexa-namine.

The pyridine rings of the title compound, C(18)H(23)N(3), are in a nearly perpendicular orientation relative to the plane defined by the three amino-bonded C atoms, making dihedral angles of 87.4 (1) ° and 84.2 (1) °. One of the pyridine N atoms acts as an hydrogen-bond acceptor for two pyridine C-H groups. By means of these intermolecular hydrogen bonds, the mol-ecules form a two-dimensional network parallel to the ab plane.

2-(3-Meth-oxy-phen-yl)-1,3-dihydro-1,3,2-benzodiaza-borole.

The title compound, C(13)H(13)BN(2)O, is one in a series of 1,3,2-benzodiaza-boroles featuring a 2-meth-oxy-phenyl substitution at the 2-position in the nitro-gen-boron heterocyle. The dihedral angle between the mean planes of the benzodiaza-borole and 2-meth-oxy-phenyl ring systems is 21.5 (1)°. There is an inter-molecular hydrogen bond between one of the NH groups and the meth-oxy O atom. This hydrogen bond leads to an infinite hydrogen-bonded chain colinear with the a axis.

1,2-Bis[(2,2':6',2''-terpyridin-4'-yl)-oxy]ethane.

The title compound, C(32)H(24)N(6)O(2), has an inversion centre located at the mid-point of the central C-C bond of the diether bridging unit. The terminal pyridine rings are canted relative to the central pyridine ring, with dihedral angles of 12.98 (6) and 26.80 (6)°. The maximum deviation from the eight-atom mean plane, defined by the two bridging O and C atoms and the central pyridine ring, is 0.0383 (10)° for the N atom.

1,6-Bis[(2,2':6',2''-terpyridin-4'-yl)-oxy]hexa-ne.

The mol-ecule of the title compound, C(36)H(32)N(6)O(2), lies about an inversion center, located at the mid-point of the central C-C bond of the diether bridge. The terminal pyridine rings form dihedral angles of 4.67 (7) and 26.23 (7)° with the central ring. In the crystal, weak C-H⋯N and C-H⋯O inter-actions link the mol-ecules into a three-dimensional network.

2-[4-(Methyl-sulfan-yl)phen-yl]naphtho[1,8-de][1,3,2]diaza-borinane.

The title compound, C(17)H(15)BN(2)S, is one member in a series of diaza-borinanes featuring substitution at the 1-, 2- and 3-positions in the nitro-gen-boron heterocycle. The dihedral angle between the mean planes of the naphthalene and phenyl ring systems is 19.86 (6)°. In the crystal structure, two C-H⋯π inter-actions link the mol-ecules into sheets which lie parallel to the bc plane. There is a π-π inter-action between each pair of centrosymmetrically related sheets [centroid-centroid distance = 3.5922 (8) Å].

2-(4-Chloro-phen-yl)naphtho-[1,8-de][1,3,2]diaza-borinane.

The title compound, C(16)H(12)BClN(2), is one in a series of diaza-borinanes, derived from 1,8-diaminona-phthalene, featuring substitution at the 1, 2 and 3 positions in the nitro-gen-boron heterocycle. The structure deviates from planarity, the torsion angle subtended by the p-chloro-phenyl ring relative to the nitro-gen-boron heterocycle being -44-.3(3)°. The mol-ecules form infinite chains with strong inter-actions between the vacant pz orbital of the B atom and the π-system of an adjacent mol-ecule. The distance between the B atom and the 10-atom centroid of an adjacent naphthalene ring is 3.381 (4) Å. One N-H H atom is weakly hydrogen bonded to the Cl atom of an adjacent mol-ecule. This combination of inter-molecular inter-actions leads to the formation of an infinite two-dimensional network perpendic-ular to the c axis.

2-Phenyl-naphtho-[1,8-de][1,3,2]diaza-borinane.

The title compound, C(16)H(13)BN(2), is one compound in a series of diaza-borinanes featuring substitution at the 1, 2 and 3 positions in the nitro-gen-boron heterocycle. The title compound is slightly distorted from planarity, with a dihedral angle of 9.0 (5)° between the mean planes of the naphthalene system and the benzene ring. The m-carbon atom of the benzene ring exhibits the greatest deviation of 0.164 (2) Šfrom the 19-atom mean plane defined by all non-H atoms. The two N-B-C-C torsion angles are 6.0 (3) and 5.6 (3)°. In the crystal, mol-ecules are linked by π-π inter-actions into columns, with a distance of 3.92 (3) Šbetween the naphthalene ring centroids. Adjacent π-stacked columns, co-linear with the b-axis, are linked by C-H⋯π inter-actions.

1-(5,7-Dihy-droxy-2,2-dimethylchroman-6-yl)ethanone.

In the title mol-ecule, C(13)H(16)O(4), the pyran ring is in a half-chair conformation. There is an intra-molecular hydrogen bond involving the ketone O atom and an H atom of a phenol group which forms an S(6) ring. The ketone O atom is also involved in an inter-molecular hydrogen bond with a different phenolic H atom of a symmetry-related mol-ecule, forming C(6) chains along the c-axis direction.

1,4-Bis[(2,2':6',2''-terpyridin-4'-yl)-oxy]butane.

The title compound, C(34)H(28)N(6)O(2), has an inversion centre located at the mid-point of the central C-C bond of the diether bridging unit. The central pyridine rings of the terpyridyl units and the diether chain are co-planar: the maximum deviation from the 18-atom mean plane defined by the bridging unit and the central pyridyl ring is for the pyridyl N atom which sits 0.055 (1) Šabove the plane. The dihedral angles between the terminal pyridine rings with this plane are 10.3 (1) and 37.6 (1)°, repectively. In the crystal, weak C-H⋯N inter-actions link the mol-ecules into infinite chains parallel to the a axis.

Self-assembled supramolecular structures of O,N,N' tridentate imidazole-phenol Schiff base compounds.

Three imidazole-derived Schiff base compounds comprising an N-methyl imidazole group coupled to a phenol ring through an imine bond were synthesised. The structures differ by the substituent on the phenol ring at the 4-position: methyl (1), tert-butyl (2) and hydrogen (3). The compounds were synthesised using both a traditional reflux in solvent as well as an environmentally friendly solid-state reaction. Compounds (1)-(3) as well as the hemihydrate of (3) were all studied by single crystal X-ray diffraction. The asymmetric unit of compound (1) consists of two nominally planar molecules linked by hydrogen bonds to form a dimeric supramolecular structure. This dimeric structure was ubiquitous for the anhydrous forms of (1)-(3). The complementary hydrogen bonding motif between the imidazole N atoms and the phenol OH results in a stable 16-membered hydrogen-bonded ring. The asymmetric unit of (3) comprises two symmetry-independent molecules one of which has co-planar imidazole and phenol rings while the other shows a significantly oblique orientation. The hemihydrate of (3) similarly forms extensive hydrogen bonds, though in the form of a water-bridged dimeric structure. The hydrogen bond lengths (D⋯A) for compounds (1)-(3) are relatively short, ranging from 2.662(1) to 2.688(1) Å. DFT was used to understand the relative stability of the monomeric and dimeric species. These showed the hydrogen-bonded supramolecular structures were ca. 101 kJ mol-1 lower in energy than the non-interacting monomers. Scan simulations were used to calculate the total energy of the molecule as a function of phenyl ring rotation and showed why the expected planar configuration for a conjugated π-system was not observed experimentally. The barrier to rotation was found to be relatively low, 7.97(6) kJ mol-1, with the lowest energy conformations subtending dihedral angles of 22.319, 24.265 and 25.319° for molecules (1), (2) and (3), respectively. The electrostatic potential maps are able to succinctly explain the stability of the hydrogen bonds through the partial charges of the interacting atoms. TD-DFT simulations and analysis of the simulated and experimental UV/visible spectra suggest that the dimeric supramolecular structure is a stable species in solution. This was confirmed through 1H NMR titrations and an equilibrium constant of 0.16(5) M-1 was estimated.

Insights into structural and physicochemical properties required for ß-hematin inhibition of privileged triarylimidazoles.

In this study, we investigated a series of triarylimidazoles, in an effort to elucidate critical SAR information pertaining to their anti-plasmodial and ß-hematin inhibitory activity. Our results showed that in addition to the positional effects of ring substitution, subtle changes to lipophilicity and imidazole ionisability were important factors in SAR interpretation. Finally, in silico adsorption analysis indicated that these compounds exert their effect by inhibiting ß-hematin crystal growth at the fast growing 001 face.

A novel trinuclear zinc(II) cluster with a tetrahedral ZnO4 core.

The reaction of 0.67 molar equivalents of the O,N,O'-tridentate zwitterionic Schiff base (2Z,4E)-4-[(2-hydroxyphenyl)iminio]pent-2-en-2-olate (H2L) with one equivalent of zinc(II) acetate in methanol affords a novel trinuclear Zn(II) cluster, di-mu-acetato-1:2kappa2O:O';2:3kappa2O:O'-dimethanol-1kappaO,3kappaO-bis{mu-2-[(2E,3Z)-4-oxidopent-3-en-2-ylideneamino]phenolato}-1:2kappa4O2,N,O4:O4;2:3kappa4O4:O2,N,O4-trizinc(II), [Zn3(C11H11NO2)2(C2H3O2)2(CH4O)2], (I), in which two bridging acetate ligands link the terminal square-based pyramidal Zn(II) ions to the approximately tetrahedral Zn(II) ion at the core of the cluster. The ZnO(4) coordination group of the central Zn(II) ion is established by two bridging phenolate and two bridging acetate O atoms. The remaining four coordination sites of each terminal Zn(II) ion are occupied by methanol and deprotonated H2L. Furthermore, the Zn-bound methanol hydroxyl groups are involved in complementary hydrogen bonding with the Zn-bound enolate O atom of a neighbouring molecule, about an inversion centre in each case. The structure of (I) is therefore best described as an extended one-dimensional hydrogen-bonded chain of trinuclear Zn(II) clusters.