Ligand-Guided Investigation of a Series of Formamidine-Based Thiuram Disulfides as Potential Dual-Inhibitors of COX-1and COX-2.

A series of thiuram disulfides 1-6 which had been previously synthesized and characterized,[1] were studied for their potential therapeutic properties. Target-fishing analyses through HitPick and SwissTarget prediction identified COX1 and COX2, which are essential biomolecules in cancer-related inflammations, as the possible targets for compounds 1 and 4 among all the compounds tested. These two proteins have enjoyed interest as targets for treating some neoplastic cancer types such as breast, colorectal, skin, pancreatic, haematological and head cancers. The inhibitory potency of 1 and 4 as lead anticancer drug candidates with dual-target ability against COX1 and COX2 was examined through molecular docking, molecular dynamics simulation and post-MD analyses such as binding energy calculation, RMSD, RMSF, and RoG. The two compounds had better docking scores and binding energies than the known inhibitors of COX1 and COX2. Insights from the RMSD, RMSF, and RoG suggested that both 1 and 4 showed observable influence on the structural stability of these targets throughout the simulation. The reported observations of the effects of 1 and 4 on the structures of COX1 and COX2 indicate their probable inhibitory properties against these target proteins and their potential as lead anticancer drug candidates.

Silver(I) pyridinyl complexes with benzothiazole, thiophene, and furan moieties: DNA/protein-binding, antibacterial, antioxidant, and anticancer studies.

We have synthesized and characterized nine Ag(I) complexes of Schiff bases containing thiophene, furan, and pyridine moieties for in vitro antibacterial, antioxidant, anticancer activities, and DNA/bovine serum albumin (BSA) binding studies. Based on the analytical and spectral analyses, a linear geometry was proposed for all the Ag(I) complexes, except for one (with the furan moiety), which formed a distorted T-shaped geometry. UV-vis absorption studies on the interactions of calf thymus-DNA (CT-DNA) with the nine Ag(I) complexes pointed to an intercalative binding mode. With a binding constant Kb of 3.75 × 105 M-1 , the complex bearing a benzothiazole moiety (1) interacted stronger with CT-DNA than the rest of the complexes. Fluorescence spectroscopic data revealed that the complexes had a modest binding affinity for BSA through static quenching. The complexes displayed good antioxidant properties, especially those with a benzothiazole moiety. Notable antibacterial activities against methicillin-resistant Staphylococcus aureus, Staphylococcus aureus, Salmonella typhimurium, Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae were observed for complexes with the furan and thiophene moieties. The in vitro anticancer studies of selected complexes against three cancer cell lines showed that the complexes were more effective against the inhibition of the growth of cervical cancer cells relative to cisplatin.

A study of structure-activity relationship and anion-controlled quinolinyl Ag(I) complexes as antimicrobial and antioxidant agents as well as their interaction with macromolecules.

In this communication, we feature the synthesis and in-depth characterization of a series of silver(I) complexes obtained from the complexation of quinolin-4-yl Schiff base ligands ((E)-2-((quinolin-4-ylmethylene)amino)phenol La, 2-(quinolin-4-yl)benzo[d]thiazole Lb, (E)-N-(2-fluorophenyl)-1-(quinolin-4-yl)methanimine Lc, (E)-N-(4-chlorophenyl)-1-(quinolin-4-yl)methanimine Ld, (E)-1-(quinolin-4-yl)-N-(p-tolyl)methanimine Le, (E)-1-(quinolin-4-yl)-N-(thiophen-2-ylmethyl)methanimine Lf) and three different silver(I) anions (nitrate, perchlorate and triflate). Structurally, the complexes adopted different coordination geometries, which included distorted linear or distorted tetrahedral geometry. The complexes were evaluated in vitro for their potential antibacterial and antioxidant activities. In addition, their interactions with calf thymus-DNA (CT-DNA) and bovine serum albumin (BSA) were evaluated. All the complexes had a wide spectrum of effective antibacterial activity against gram-positive and gram-negative bacterial and good antioxidant properties. The interactions of the complexes with CT-DNA and BSA were observed to occur either through intercalation or through a minor groove binder, while the interaction of the complexes with BSA reveals that some of the complexes can strongly quench the fluorescence of BSA through the static mechanism. The molecular docking studies of the complexes were also done to further elucidate the modes of interaction with CT-DNA and BSA.

Quinoline Functionalized Schiff Base Silver (I) Complexes: Interactions with Biomolecules and In Vitro Cytotoxicity, Antioxidant and Antimicrobial Activities.

A series of fifteen silver (I) quinoline complexes Q1-Q15 have been synthesized and studied for their biological activities. Q1-Q15 were synthesized from the reactions of quinolinyl Schiff base derivatives L1-L5 (obtained by condensing 2-quinolinecarboxaldehyde with various aniline derivatives) with AgNO3, AgClO4 and AgCF3SO3. Q1-Q15 were characterized by various spectroscopic techniques and the structures of [Ag(L1)2]NO3Q1, [Ag(L1)2]ClO4Q6, [Ag(L2)2]ClO4Q7, [Ag(L2)2]CF3SO3Q12 and [Ag(L4)2]CF3SO3Q14 were unequivocally determined by single crystal X-ray diffraction analysis. In vitro antimicrobial tests against Gram-positive and Gram-negative bacteria revealed the influence of structure and anion on the complexes' moderate to excellent antibacterial activity. In vitro antioxidant activities of the complexes showed their good radical scavenging activity in ferric reducing antioxidant power (FRAP). Complexes with the fluorine substituent or the thiophene or benzothiazole moieties are more potent with IC50 between 0.95 and 2.22 mg/mL than the standard used, ascorbic acid (2.68 mg/mL). The compounds showed a strong binding affinity with calf thymus-DNA via an intercalation mode and protein through a static quenching mechanism. Cytotoxicity activity was examined against three carcinoma cell lines (HELA, MDA-MB231, and SHSY5Y). [Ag(L2)2]ClO4Q7 with a benzothiazole moiety and [Ag(L4)2]ClO4Q9 with a methyl substituent had excellent cytotoxicity against HELA cells.

Knowledge of Obstetric and Neonatal Danger Signs among Community Health Workers in the Rongo Sub-County of Migori County, Kenya: Results of a Community-based Cross-Sectional Survey.

In efforts to reduce maternal and neonatal mortality, it is recommended that all pregnant women be counseled on signs of pregnancy related complications and neonatal illness. In resource limited settings, such counselling may be task-shifted to lay health workers. We conducted a community-based cross-sectional survey of community health workers/volunteers in North and East Kamagambo of the Rongo Sub- County of Migori County, Kenya, between January-April 2018. A survey tool was administered through face-to-face interviews to investigate the level of knowledge of obstetric and neonatal danger signs among community health workers in North Kamagambo after one year of participation in the Lwala program, as well as to evaluate baseline knowledge of community health volunteers in East Kamagambo at the beginning of Lwala's expansion and prior to their receiving training from Lwala. The North Kamagambo group identified more danger signs in each category. The percentage of participants with adequate knowledge in the pregnancy, postpartum, and neonatal categories was significantly higher in North Kamagambo than in East Kamagambo. Sixty percent of participants in North Kamagambo knew 3 or more danger signs in 3 or more categories, compared to 24% of participants in East Kamagambo. Location in North Kamagambo (OR 2.526, p=0.03) and a shorter time since most recent training (OR 2.291, p=0.025) were associated with increased knowledge. Our study revealed varying levels of knowledge among two populations of lay health workers. This study highlights the benefit of frequent trainings and placing greater emphasis on identified gaps in knowledge of the labor and postpartum periods.

Architecture and synthesis of P,N-heterocyclic phosphine ligands.

Diverse P,N-phosphine ligands reported to date have performed exceptionally well as auxiliary ligands in organometallic catalysis. Phosphines bearing 2-pyridyl moieties prominently feature in literature as compared to phosphines with five-membered N-heterocycles. This discussion seeks to paint a broad picture and consolidate different synthetic protocols and techniques for N-heterocyclic phosphine motifs. The introduction provides an account of P,N-phosphine ligands, and their structural and coordination benefits from combining heteroatoms with different basicity in one ligand. The body discusses the synthetic protocols which focus on P-C, P-N-bond formation, substrate and nucleophile types and different N-heterocycle construction strategies. Selected references are given in relation to the applications of the ligands.

The effect of 1:2 Ag(I) thiocyanate complexes in MCF-7 breast cancer cells.

There is much interest currently in the design of metal compounds as drugs and various metal compounds are already in clinical use. These include gold(I) compounds such as auranofin and the anti-cancer platinum(II) complex, cisplatin. Bis-chelated gold(I) phosphine complexes have also shown great potential as anticancer agents, however, their efficacy has been limited by their high toxicity. In this study, silver(I) thiocyanate compounds linked to four specific ligands, were synthesized and characterized. These silver-phosphine adducts included [AgSCN{P(4-MeC6H4)3}2]2 (1); [AgSCN{P(4-ClC6H4)3}2]2 (2); [AgSCN{P(4-MeOC6H4)3}2]2 (3); [AgSCN(PPh3)2]2 (4). The compounds were found to be toxic to MCF-7 breast cancer cells while the ligands on their own were not toxic. Our findings further indicate that the silver(I) phosphine compounds induce apoptotic cell death in these breast cancer cells. In addition, the compounds were not toxic to nonmalignant fibroblast cells at the IC50 concentrations. This is an indication that the compounds show selectivity towards the cancer cells.

The induction of cell death by phosphine silver(I) thiocyanate complexes in SNO-esophageal cancer cells.

Esophageal cancer is one of the least studied cancers and is found to be prominent in black South African males. It is mainly diagnosed in the late stages, and patients tend to have a low 5-year survival rate of only 10%. Silver is generally used as an antimicrobial agent, with limited reports on anticancer studies. In this study, dimeric silver(I) thiocyanate complexes were used containing a variation of 4-substitued triphenylphosphines, including [AgSCN(PPh(3))(2)](2) (1), [AgSCN{P(4-MeC(6)H(4))(3)}(2)](2) (2), [AgSCN{P(4-FC(6)H(4))(3)}(2)](2) (3) and [AgSCN{P(4-ClC(6)H(4))(3)}(2)](2) (4). All four complexes, with their respective phosphine ligands, PPh(3) (L1), P(4-MeC(6)H(4))(3) (L2), P(4-FC(6)H(4))(3) (L3) and P(4-ClC(6)H(4))(3) (L4), were subjected to in vitro toxicity studies in SNO-esophageal cancer cells, using an alamarBlue(®) assay. Morphological changes, including blebbing and apoptotic body formation, were observed. Phosphatidylserine externalization, a marker of apoptosis, was quantified by flow cytometry. The phosphine ligands L1-L4, on their own, had minimal effect on the malignant while complexes 1-4 resulted in significant cell death. A 10x decreased concentration of these complexes had similar effects than cisplatin, used as the positive control. These complexes show promise as anticancer agents.

The double-stranded ladder-like structure of poly[[bis(µ2-acetato-κ(2)O:O')bis(acetato-κO)bis(µ-4,4'-bipyridine-κ(2)N:N')dicopper(II)] 4-nitrophenol disolvate tetrahydrate].

The reaction of 4,4'-bipyridine with copper acetate in the presence of 4-nitrophenol led to the formation of the title compound, {[Cu(CH3COO)2(C10H8N2)]·C6H5NO3·2H2O}n. The complex forms a double-stranded ladder-like coordination polymer extending along the b axis. The double-stranded polymers are separated by 4-nitrophenol and water solvent molecules. The two Cu(II) centres of the centrosymmetric Cu2O2 ladder rungs have square-pyramidal coordination environments, which are formed by two acetate O atoms and two 4,4'-bipyridine N atoms in the basal plane and another acetate O atom at the apex. The ladder-like double strands are separated from each other by one unit-cell length along the c axis, and are connected by the water and 4-nitrophenol molecules through a series of O-H···O and C-H···O hydrogen-bonding interactions and two unique intermolecular π-π interactions.

Di-µ-chlorido-bis-{[2-(di-tert-butyl-phosphan-yl)biphenyl-3-yl-κ(2)C(3),P]palladium(II)} dichloro-methane disolvate.

The asymmetric unit of the title compound, [Pd(2)Cl(2)(C(20)H(26)P)(2)]·2CH(2)Cl(2), contains one half-mol-ecule of the palladium complex and a dichloro-methane solvent mol-ecule. In the complex, two Pd(II) atoms are bridged by two Cl atoms, with the other two coordination sites occupied by a C atom of the biphenyl system and a P atom, resulting in a distorted square-planar coordination geometry of the Pd(II) atom and a cyclo-metallated four-membered ring. The Pd(2)Cl(2) unit is located about an inversion center. The planes of the rings of the biphenyl system make a dihedral angle of 66.36 (11)°.

1-(5-Hy-droxy-2,2,8,8-tetra-methyl-2H,8H-pyrano[2,3-f]chromen-6-yl)-3-(4-meth-oxy-phen-yl)prop-2-en-1-one.

In the biologically active title compound, C26H26O5, the pyran ring of the chromene unit adopts a half-chair conformation. The C=C double bond of the propenone unit exhibits a trans conformation and the carbonyl group is syn conformation to the double bond. The dihedral angle between the benzene ring and the benzopyran-one moiety is 31.54 (4)°. The mol-ecular structure is stabilized by an intra-molecular C=O⋯H-O hydrogen bond.

Ring-opening polymerization of lactides and ε-caprolactone catalyzed by Zn(II) aryl carboxylate complexes supported by 4-pyridinyl schiff base ligands.

Synthesis and catalytic studies of aryl carboxylate Zn (II) complexes is reported. Reaction of substituted (E)-N-phenyl-1-(pyridin-4-yl)methanimine with a methanolic solution of Zn(CH3COO)2 and substituted aryl carboxylate co-ligands gave heteroleptic Zn(II) complexes; [Zn(C6H5COO)2(L1)]2 (1), [Zn(C7H7COO)2(L1)]2 (2), [Zn (4-F-C6H4COO)2(L1)]2 (3), [Zn(C6H5COO)2(L2)]2 (4), [Zn(C7H7COO)2(L2)]2 (5), [Zn (4-F-C6H4COO)2(L2)]2 (6), [Zn(C6H5COO)2(L3)]2 (7), [Zn(C7H7COO)2(L3)]2 (8), [Zn (4-F-C6H4COO)2(L3)]2 (9). The molecular structures of complexes 1 and 4 are dinuclear with the zinc atom in complex 1 adopting a distorted trigonal bipyramidal geometry in a bi-metallacycle while complex 4 is square pyramidal where all four benzoate ligands bridge the zinc metals in a paddle wheel arrangement. All complexes successfully initiated mass/bulk ring-opening polymerization (ROP) of ϵ-caprolactone (ϵ-CL) and lactides (LAs) monomers with or without alcohol co-initiators at elevated temperatures. Complexes 1, 4 and 6 containing the unsubstituted benzoate co-ligands were the most active in their triad; with complex 4 being the most active (k app) of 0.3450 h-1. The physicochemical properties of the polymerization products of l-lactide and rac-lactide in toluene revealed melting temperatures (Tm) between 116.58 °C and 188.03 °C, and decomposition temperatures between 278.78 °C and 331.32 °C suggestive of an isotactic PLA with a metal capped end.

The link between relative stability constant of DNA- and BSA-chromenopyrimidine complexes and cytotoxicity towards human breast cancer cells (MCF-7).

In this study, we synthesized and characterized ten chromenopyrimidine derivatives using analytical and spectroscopic methods. Studies on DNA and albumin binding affinity, as well as cytotoxicity tests on human breast cancer (MCF-7) cells, of the chromenopyrimidines, were conducted. The natural logarithm of the relative stability constant of DNA- and BSA-chromenopyrimidine complexes [ln(KDNA/KBSA)] was used as a criterion for selecting compounds for cytotoxicity studies. We found that ln(KDNA/KBSA) was inversely related to IC50 values of the compounds in MCF-7 cells. The antiproliferative effects of the compounds were found to induce apoptosis in MCF-7 cells, which is a desired mechanism of cell death. Correlations between the DNA and albumin binding affinities of chromenopyrimidines were established. We propose that this relationship approach can, for a given set of compounds, assist in predicting the cytotoxicity of potential drug candidates towards MCF-7 cells based on their experimentally determined CT-DNA and BSA binding affinities.

N-(2,6-Diisopropyl-phen-yl)thio-amide.

In the crystal structure of the title compound, C(13)H(19)NS {systematic name: N-[2,6-bis-(propan-2-yl)phen-yl]carbothio-amide}, mol-ecules assemble via N-H⋯S=C hydrogen bonds into helical chains along the b axis. The thio-amide moiety, with a syn disposition of the N- and C-bound H atoms, is twisted out of the plane of the benzene ring to which it is connected, forming a dihedral angle angle of 77.60 (14)°.

1-(Ferrocen-1-ylmeth-yl)-3-methyl-imidazol-3-ium iodide.

The structure of the title compound, [Fe(C5H5)(C10H12N2)]I, consists of a 1-(ferrocen-1-ylmeth-yl)-3-methyl-imidazolium cation which is counter-balanced by an iodide anion. The cyclo-penta-dienyl (Cp) rings of the ferrocene unit have a slightly staggered conformation skewed from an ideal eclipsed conformation by an angle of 3.5 (6)°. The inter-planar angle between the Cp and the imidazole ring is 67.94 (2)°.

Bis[O-methyl (4-eth-oxy-phen-yl)dithio-phospho-nato-κ(2) S,S']nickel(II).

In the title compound, [Ni(C9H12O2PS2)2], the Ni(II) atom resides on an inversion center and is coordinated by four S atoms [Ni-S = 2.2328 (4) and 2.2455 (3) Å] in a distorted square-planar geometry [S-Ni-S = 88.443 (13) and 91.557 (13)°]. In the crystal, mol-ecules related by translation in [110] are linked into chains via weak C-H⋯O inter-actions. The crystal packing exhibits short inter-molecular S⋯S contacts of 3.3366 (5) Å.

Bis[O-propyl (4-eth-oxy-phen-yl)dithio-phospho-nato-κ(2) S,S']nickel(II).

The title compound, [Ni(C11H16O2PS2)2], contains a four-coordinate Ni(II) cation with an idealized square-planar geometry. The metal atom is surrounded by two chelating isobidentate dithio-phospho-nate ligands in a trans or anti configuration, binding through the S-donor atoms.

(4-{[(Pyridin-4-yl)methyl-idene]amino}-phen-yl)ferrocene.

The asymetric unit of the title compound, [Fe(C5H5)(C17H13N2)], contains two independent mol-ecules whose conformations differ, especially in the 4-{(pyridin-4-yl)methyl-idene]amino}-phenyl unit where one is flipped by almost 180°. The cyclo-penta-dienyl rings of the ferrocene unit also exhibit different staggered conformations: in one mol-ecule the conformation is staggered by 9.43 (2)° and in the other by 24.46 (1)° from an ideal eclipsed geometry. The plane of the benzene ring is tilted away from the ferrocene group in both mol-ecules, with dihedral angles of 6.97 (1) and 10.30 (2)°. The benzene ring is also slightly twisted from the plane of the pyridine ring, with dihedral angles of 5.98 (2) and 6.51 (2)° in the two mol-ecules.

N,N-Bis(diphenyl-thio-phosphino-yl)-4-ethyl-aniline.

The title compound, C32H29NP2S2, has two mol-ecules in the asymmetric unit, with an r.m.s. difference of 0.218 Šin their best-fit overlay. Both mol-ecules have a slightly distorted trigonal-planar N atom, bonded to two P(V) atoms and a C atom of the 4-ethyl-phenyl unit. The P-N-P angles of 126.34 (11) and 125.98 (11)° are larger than the four C-N-P bond angles. The two S atoms are trans to one another with respect to the P-N-P angle. The crystal structure features C-H⋯π inter-actions. The methyl group in one of the mol-ecules is disordered over two sets of sites, with occupancies of 0.518 (6) and 0.482 (6).

1-(5-Hy-droxy-2,2,8,8-tetra-methyl-2H,8H-pyrano[2,3-f]chromen-6-yl)ethanone.

In the title compound, C(18)H(20)O(4),the pyran ring of the chromene unit adopts a half-chair conformation. An intra-molecular O-H⋯O hydrogen bond occurs. In the crystal, mol-ecules are linked along the b axis by C-H⋯O hydrogen bonds.