Dinuclear and mononuclear metal(II) polypyridyl complexes against drug-sensitive and drug-resistant Plasmodium falciparum and their mode of action.

BACKGROUND: Malaria remains one of the most virulent and deadliest parasitic disease in the world, particularly in Africa and Southeast Asia. Widespread occurrence of artemisinin-resistant Plasmodium falciparum strains from the Greater Mekong Subregion is alarming. This hinders the national economies, as well as being a major drawback in the effective control and elimination of malaria worldwide. Clearly, an effective anti-malarial drug is urgently needed. METHODS: The dinuclear and mononuclear copper(II) and zinc(II) complexes were synthesized in ethanolic solution and characterized by various physical measurements (FTIR, CHN elemental analysis, solubility, ESI-MS, UV-Visible, conductivity and magnetic moment, and NMR). X-ray crystal structure of the dicopper(II) complex was determined. The in vitro haemolytic activities of these metal complexes were evaluated spectroscopically on B+ blood while the anti-malarial potency was performed in vitro on blood stage drug-sensitive Plasmodium falciparum 3D7 (Pf3D7) and artemisinin-resistant Plasmodium falciparum IPC5202 (Pf5202) with fluorescence dye. Mode of action of metal complexes were conducted to determine the formation of reactive oxygen species using PNDA and DCFH-DA dyes, JC-1 depolarization of mitochondrial membrane potential, malarial 20S proteasome inhibition with parasite lysate, and morphological studies using Giemsa and Hoechst stains. RESULTS: Copper(II) complexes showed anti-malarial potency against both Pf3D7 and Pf5202 in sub-micromolar to micromolar range. The zinc(II) complexes were effective against Pf3D7 with excellent therapeutic index but encountered total resistance against Pf5202. Among the four, the dinuclear copper(II) complex was the most potent against both strains. The zinc(II) complexes caused no haemolysis of RBC while copper(II) complexes induced increased haemolysis with increasing concentration. Further mechanistic studies of both copper(II) complexes on both Pf3D7 and Pf5202 strains showed induction of ROS, 20S malarial proteasome inhibition, loss of mitochondrial membrane potential and morphological features indicative of apoptosis. CONCLUSION: The dinuclear [Cu(phen)-4,4'-bipy-Cu(phen)](NO3)4 is highly potent and can overcome the total drug-resistance of Pf5202 towards chloroquine and artemisinin. The other three copper(II) and zinc(II) complexes were only effective towards the drug-sensitive Pf3D7, with the latter causing no haemolysis of RBC. Their mode of action involves multiple targets.

Sialic acid detection and theranostic activity of phenylboronic acid-based fluorescent probe in human colorectal adenocarcinoma HT-29 cells.

A new probe, 4-(((3',6'-bis(diethylamino)-3-oxospiro[isoindoline-1,9'-xanthen]-2-yl)imino)methyl)phenyl)boronic acid (R4B) was prepared by facile condensation of 4-formylphenylboronic acid and rhodamine B hydrazide. R4B was characterized by spectroscopic methods and single crystal X-ray diffraction. The sensor R4B solution turned pink and emitted orange fluorescence only in the presence of sialic acid but remained colorless and non-fluorescent otherwise. The sugar recognition performance was investigated via UV-vis and fluorescence spectroscopic studies. Our results revealed that R4B has good affinity and selectivity for sialic acid over common monosaccharides, with a detection limit as low as 10-7 M. Furthermore, R4B selectively inhibited growth of human colorectal adenocarcinoma HT-29 (IC50 <20 µM) without significant cytotoxicity to normal human colon fibroblasts CCD-18Co. Treatment with R4B suppressed HT-29 colony formation via mitochondrial apoptosis in a time-dependent manner. Cellular imaging studies also revealed the ability of R4B as a fluorescence dye to detect intracellular sialic acid and showed mitochondria-tracking ability in HT-29 cells. In summary, R4B is a potential theranostic for the detection of intracellular sialic acid during the early incubation period, followed by induction of cancer apoptotic cell death at a later treatment point.

Synthesis, Structural Characterization, Hirshfeld Surface Analysis, and Antibacterial Study of Pd(II) and Ni(II) Schiff Base Complexes Derived from Aliphatic Diamine.

A Schiff base bearing two methyl substituents, namely, 6,6'-((1E,1'E)-((2,2-dimethylpropane-1,3-diyl) bis(azanylylidene)) bis(methanylylidene)) bis(2-methylphenol) [H2AD1Me] was synthesized and characterized through physicochemical and spectroscopic analyses. Then, the Schiff base was complexed with Pd(II) and Ni(II) to form [Pd(AD1Me)] and [Ni(AD1Me)], respectively. Both metal complexes were successfully obtained and characterized through several analyses, viz., melting point, elemental analysis, molar conductivity, magnetic susceptibility, FTIR, 1H NMR, UV-vis, and single crystal X-ray diffraction. A quantitative analysis of the intermolecular interactions in the crystal structures has been performed using Hirshfeld surface analysis. Both metal complexes were crystallized in a monoclinic crystal system with the space group of P21/c. Additionally, the deprotonated phenolic oxygen atom (O1/O2) and azomethine nitrogen atom (N1/N2) of the ligand chelate the Pd(II) and Ni(II) ions, forming a slightly distorted square-planar complex containing three six-membered rings encircling the metal core with dsp2 hybridization. The shift of ν(C=N) to a higher frequency in FTIR by 26-28 cm-1 indicated that the complexation to Pd(II) and Ni(II) through the azomethine N was established. It was further supported through the shifting of the azomethine proton signal to higher or lower chemical shifts with Δδ = 0.43-1.15 ppm in 1H NMR. In addition, the shifting of the n-π*(C=N) band in UV-vis spectra with Δλ = 24-40 nm indicated the involvement of azomethine nitrogen in the complexation. All the compounds showed no significant antibacterial activity against three bacterial strains, namely, Staphylococcus aureus subsp. aureus Rosenbach (ATCC 6538), Streptococcus mutans Clarke (ATCC 700,610), and Proteus vulgaris (ATCC 6380), as the percent growth inhibition calculated was less than 90%.

[3-({(E)-2-[(4-Fluorophenyl)carbamo-thioyl]hydrazinylidene}methyl)-4-hy-droxy-benzyl]methyl-triphenyl-phos-phonium chloride.

The cation in the title salt, C(33)H(28)FN(3)OPS(+)·Cl(-), is highly twisted with the phospho-nium group occupying a position almost normal to the central hydroxyl-benzene ring [P-C-C-C tosrsion angle = -100.9 (3)°], and with the hydrazone substituent twisted out of the plane [C-C-C-N torsion angle = 13.1 (4)°]. The fluoro-benzene ring is twisted out of the plane of the adjacent thio-urea residue, forming a dihedral angle of 51.69 (10)°. The configuration about the C=N bond [1.281 (4) Å] is E, the O-H and N-H hydrogen atoms are syn, and in the thio-urea residue, the N-H hydrogen atoms are anti, allowing for the formation of an intra-molecular N-H⋯N hydrogen bond. In the crystal, dimeric aggregates mediated by N-H⋯S bonds are formed, which are linked to the Cl(-) anions by O-H⋯Cl hydrogen bonds. The four-component aggregates are linked into a three-dimensional structure by C-H⋯Cl inter-actions.

A rhodamine based chemosensor for solvent dependent chromogenic sensing of cobalt (II) and copper (II) ions with good selectivity and sensitivity: Synthesis, filter paper test strip, DFT calculations and cytotoxicity.

A new chemosensor 1 was synthesized by reacting rhodamine B hydrazide and 2,3,4-trihydroxybenzaldehyde, which was then characterized by spectroscopic techniques and single crystal X-ray crystallography. Sensor 1 has the ability to sense Co2+/Cu2+ ions by "naked-eye" with an apparent colour change from colourless to pink in different solvent system, MeCN and DMF respectively. Furthermore, it can selectively detect Co2+/Cu2+ among wide range of different metal ions, and it exhibits low detection limit of 4.425 × 10-8 M and 1.398 × 10-7 M respectively. Binding mode of the two complexes were determined to be 1:1 stoichiometry for Co2+ complex and 1:2 stoichiometry for Cu2+ complex through Job's plot, IR spectroscopy, mass spectrometry and 1H NMR spectroscopy. Moreover, reversibility of the sensor 1 as copper (II) ion detector was determined by using EDTA and the results showed that sensor 1 can be reused for at least 6 cycles. Other than that, a low cost chemosensor test strips were fabricated for the convenient "naked-eye" detection of Co2+ and Cu2+ in pure aqueous media. The MTT assay was conducted in order to determine the cytotoxicity of sensor 1 towards human cell lines.

Crystal structure, DNA binding studies, nucleolytic property and topoisomerase I inhibition of zinc complex with 1,10-phenanthroline and 3-methyl-picolinic acid.

Crystal structure analysis of the zinc complex establishes it as a distorted octahedral complex, bis(3-methylpicolinato-kappa(2) N,O)(2)(1,10-phenanthroline-kappa(2) N,N)-zinc(II) pentahydrate, [Zn(3-Me-pic)(2)(phen)]x5H(2)O. The trans-configuration of carbonyl oxygen atoms of the carboxylate moieties and orientation of the two planar picolinate ligands above and before the phen ligand plane seems to confer DNA sequence recognition to the complex. It cannot cleave DNA under hydrolytic condition but can slightly be activated by hydrogen peroxide or sodium ascorbate. Circular Dichroism and Fluorescence spectroscopic analysis of its interaction with various duplex polynucleotides reveals its binding mode as mainly intercalation. It shows distinct DNA sequence binding selectivity and the order of decreasing selectivity is ATAT > AATT > CGCG. Docking studies lead to the same conclusion on this sequence selectivity. It binds strongly with G-quadruplex with human tolemeric sequence 5'-AG(3)(T(2)AG(3))(3)-3', can inhibit topoisomerase I efficiently and is cytotoxic against MCF-7 cell line.

Bis[(4-chloro-benz-yl)triphenyl-phospho-nium] tetra-chloridozincate(II) trihydrate.

The crystal structure of the title compound, (C(25)H(21)ClP)(2)[ZnCl(4)]·3H(2)O, consists of tetra-hedral phosphonium cations and tetra-hedral zincate anions; the water mol-ecules form weak hydrogen bonds to the anions. Two of the water mol-ecules are disordered over three sites in a 0.68:0.55:0.77 ratio.

5-Ethyl-5-methyl-4-phenyl-5H-1,2,4-triazol-3(4H)-thione.

The five-membered ring of the title compound Δ(1)-1,2,4-triazoline-5-thione, C(11)H(13)N(3)S, is almost planar (r.m.s. deviation = 0.009 Å); the phenyl ring is aligned at 84.6 (2)° with respect to the five-membered ring. The crystal studied was a racemic twin with an approximate 20% minor twin component. Weak inter-molecular C-H⋯N hydrogen bonding is present in the crystal structure.

Bis(µ-5-hydr-oxy-2-{[2-(N-phenyl-thio-carbamo-yl)hydrazin-1-yl-idene]meth-yl}phenolato)bis[chloridozinc(II)] N,N-dimethyl-formamide tetra-solvate.

In the dinuclear title compound, [Zn(2)(C(14)H(12)N(3)O(2)S)(2)Cl(2)]·4C(3)H(7)NO, the two monodeprotonated Schiff base ligands N,O,S:O-chelate to Zn atoms. The formally negatively charged O atom involved in chelation also serves as a bridge. The O, O', N and S atoms comprise a square, and the Cl atom the apex of a square pyramid surrounding each metal atom. The solvate dimethyl-formamide mol-ecules, one of which is disordered over two positions in a 3:1 ratio, are hydrogen bonded to the dinuclear mol-ecule.

2,4,6,8-Tetra-kis(4-ethyl-phen-yl)-3,7-diaza-bicyclo-[3.3.1]nonan-9-one.

The bicyclo-[3.3.1]nonane ring in the title compound, C(39)H(44)N(2)O, adopts a chair-boat conformation with the four benzene rings being directed away from the carbonyl group. The presence of C-H⋯O contacts leads to helical supra-molecular chains along the b axis.

4-[(3,4-Dimeth-oxy-benzyl-idene)amino]-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one.

The imino-carbon double-bond in the title Schiff base, C(20)H(21)N(3)O(3), has an E configuration; the six-membered aromatic substituent (r.m.s. deviation = 0.012 Å) is nearly coplanar with five-membered pyrazole substituent (r.m.s. deviation = 0.031 Å), the dihedral angle between the two systems being 11.4 (1)°]. The phenyl ring connected to the pyrazole ring is aligned at 45.5 (1)° with respect to this five-membered ring. The N atoms in the ring show pyramidal coordinations.

trans-3-(3,4-Dimeth-oxy-phen-yl)-2-(4-nitro-phen-yl)prop-2-ene-nitrile.

The asymmetric unit of the title compound, C(17)H(14)N(2)O(4), contains two independent mol-ecules in which the benzene rings are in a trans arrangement with respect to the C=C double bond and the rings are inclined by 4.3 (1) and 22.1 (1)° with respect to each other.

4-{[4-(Dimethylamino)benzylidene]-amino}-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one.

The azomethine double-bond in the title Schiff base, C(20)H(22)N(4)O, has an E-configuration. The aromatic ring of the benzyl-idene portion (r.m.s. deviation 0.011 Å) and the five-membered pyrazolyl ring (r.m.s. deviation 0.033 Å) form a dihedral angle of 19.0 (1)°. The phenyl substituent is twisted by 55.0 (1)° with respect to the five-membered ring.

4-Nitroaniline-2,4,6-trimethoxybenz-aldehyde (1/1).

In the title co-crystal, C(6)H(6)N(2)O(2.)C(10)H(12)O(4), the two components are held together by an N-H⋯O(aldehyde) hydrogen bond. Adjacent co-crystals are linked by weaker N-H⋯O(nitro) hydrogen bonds, forming a linear chain. The two aromatic rings of the components are aligned at 75.2 (1)°. The crystal studied was a non-merohedral twin with a 24% minor component.

(2E)-1-(6-Chloro-2-methyl-4-phenyl-quinolin-3-yl)-3-phenyl-prop-2-en-1-one.

In the title compound, C(25)H(18)ClNO, the conformation about the C=C double bond is E. Significant twists are evident in the mol-ecule, with the benzene ring forming a dihedral angle of 53.92 (11)° with the quinolinyl residue. Further, the chalcone residue is approximately perpendicular to the quinolinyl residue [C(q)-C(q)-C(c)-O(c) torsion angle = -104.5 (3)°, where q = quinolinyl and c = chalcone]. In the crystal, the presence of C-H⋯O and C-H⋯π inter-actions leads to supra-molecular layers lying parallel to (02).

4-[(9-Ethyl-9H-carbazol-3-yl)methyl-idene-amino]-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one.

The imino-carbon double bond in the title Schiff base, C(26)H(24)N(4)O, has an E configuration. The 13-membered carbazolyl fused-ring (r.m.s. deviation = 0.056 Å) is nearly coplanar with five-membered pyrazole ring (r.m.s. deviation = 0.036 Å) [dihedral angle between the two systems = 10.4 (1)°]; the phenyl substituent is twisted by 51.1 (1)° with respect to the five-membered ring.

N-[4-(Dimethyl-amino)-benzyl-idene]-3,4-dimethyl-isoxazol-5-amine.

The aromatic rings attached to the azomethine double bond in the title compound, C(14)H(17)N(3)O, are trans to each other [C-C=N-C torsion angle = 179.5 (1)°], and they are approximately coplanar [dihedral angle between the five- and six-membered rings = 13.7 (1)°].

A monoclinic modification of 2-[(1,3-benzothia-zol-2-yl)imino-meth-yl]phenol.

In the title Schiff base, C(14)H(10)N(2)OS, the azomethine double bond is in an E configuration; the benzothiazolyl ring (r.m.s. deviation = 0.007 Å) is coplanar with the phenyl-ene ring (r.m.s. deviation = 0.007 Å), the two rings being slightly bent at 2.6 (1)°. The hy-droxy H atom forms an intra-molecular hydrogen bond to the imino group. The bond dimensions of the monoclinic modification are similar to those of the ortho-rhom-bic modification [Liu et al. (2009 ▶). Acta Cryst. E65, o738].

N-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)acetamide-naphthalene-2,3-diol (1/1).

In the reaction of naphthalene-2,3-diol and 4-amino-anti-pyrine in the presence of acetic acid, the amine function is acetyl-ated and the resulting acetamide co-crystallizes with the diol in the title compound, C(13)H(15)N(3)O(2)·C(10)H(8)O(2), with 1:1 molar stoichiometry. The two components are linked by two O-H⋯O=C hydrogen bonds. One of the hy-droxy groups inter-acts with the pyrazolone carbonyl O atom and the other hy-droxy group inter-acts with the amide O atom of another component, generating a chain motif. Adjacent chains are linked into a layer motif via N-H⋯O inter-actions involving only the heterocyclic acetamide component.

Diaqua-(1,4,8,11-tetra-aza-cyclo-tetra-decane-κN,N,N,N)copper(II) dihepta-noate dihydrate.

The Cu(II) atom in the title salt, [Cu(C(10)H(24)N(4))(H(2)O)(2)][CH(3)(CH(2))(5)CO(2)](2)·2H(2)O, is chelated by the four N atoms of the 1,4,8,11-tetra-aza-cyclo-tetra-decane (cyclam) ligand and is coordinated by two water mol-ecules in a tetra-gonally Jahn-Teller-distorted octa-hedral geometry. The Cu(II) atom lies on a center of inversion. The cations, anions and uncoordinated water mol-ecules are linked by N-H⋯O and O-H⋯O hydrogen bonds, forming a layer structure parallel to (100). The alkyl chain of the anion is disordered over two positions in a 0.82 (1):0.18 (1) ratio.