Investigation on the pharmacological profile of antimony(III) complexes with hydroxyquinoline derivatives: anti-trypanosomal activity and cytotoxicity against human leukemia cell lines

Complexes [Sb(QN)₂Cl] (1), [Sb(QC)₂Cl] (2) and [Sb(QI)₂Cl] (3) were obtained with 8-hydroxyquinoline (HQN), 5-chloro-8-hydroxyquinoline (HQC) and 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol, HQI). The quinoline derivatives and their antimony(III) complexes were evaluated for their anti-trypanosomal activity as well as for their cytotoxicity against HL-60 and Jurkat human leukemia cell lines. Upon coordination to antimony(III) the anti-trypanosomal activity of HQC and HQI increases, the highest improvement being observed for complex (3), which was the most active among all studied compounds against both epimastigote and trypomastigote forms of Trypanosoma cruzi. All quinoline derivatives proved to be cytotoxic against both leukemia cell lineages. Upon coordination to antimony(III) the cytotoxicity of HQN improved against Jurkat leukemia cells. While SbCl₃ proved to be cytotoxic against HL-60 cells, it was not active against Jurkat cells. However, its coordination to the quinoline derivatives resulted in complexes with significant cytotoxicity against Jurkat cells.     

Therapeutic properties and molecular docking study of some phenolic compounds as anti-human lung cancer potential: A biochemical approach

Chloroxine (5,7-dichloro-8-hydroxyquinoline) is a molecule utilized in some shampoos for the therapy of seborrheic dermatitis of the scalp and dandruff. In this study, we investigated the inhibition effects of 5,7-dichloro-8-hydroxyquinoline and methyl 3,4,5-trihydroxybenzoate compounds on the 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA Reductase) and urease enzymes. We have obtained results for the HMG-CoA Reductase and urease enzymes at the micromolar level. In our study, inhibition result of 5,7-dichloro-8-hydroxyquinoline and Methyl 3,4,5-trihydroxybenzoate on HMG-CoA reductase showed lower values 2.28 ± 0.78 and 33.25 ± 5.04 µg/ml, respectively. Additionally, inhibition result of 5,7-dichloro-8-hydroxyquinoline and methyl 3,4,5-trihydroxybenzoate on urease showed lower values 6.18 ± 1.38 and 8.51 ± 1.35 µg/ml, respectively. Molecular docking calculations were made for their biological activities were compared. In the present work, the structures of the related compounds ( 1 and 2 ) were drawn using Gaussian 09 software and done geometry optimization at DFT/B3LYP/6-31G* basis set with aforementioned program. Cytotoxicity potential of these compounds against human lung cancer demonstrated that these compounds had good cytotoxic effects. Both compounds significantly decreased lung cell viability from low doses. In addition, 100 µM dose of all compounds caused significant reductions in lung cell viability. In general, we can say that of the two tested compounds, 5,7-dichloro-8-hydroxyquinoline and methyl 3,4,5-trihydroxybenzoate have cytotoxic effects in all cell types, and this effect is particularly strong in lung cells. Activities were performed at concentrations of 10, 20, 50, 70, and 100 µl and we achieved good results. Lung cell viability (%) value was better at 100 µl concentration and IC₅₀ of them were 54.28 and 48.05 µM.     

Red to near-infrared electrophosphorescence from an iridium complex coordinated with 2-phenylpyridine and 8-hydroxyquinoline

An iridium complex coordinated with 2-phenylpyridine (ppy) and 8-hydroxyquinoline (q), ppy₂Irq, was synthesized and its thermal stability, absorption, photoluminescence, crystal structure and electrophosphorescence were characterized. The melting point of this material reaches as high as 374 °C and does not suffer decomposition upon heating at high vacuum therefore can be well sublimated. When ppy₂Irq was used as a guest emitting material in the electrophosphorescent device, the emission is 100% saturated red light starting at ∼600 nm, extending into the near-infrared region. The bathochromic shift, compared to the fluorescence and phosphorescence from Alq₃, Ptq₂ and Ir(ppy)₃, was analyzed to originate from the triplet excited state of 8-hydroxyquinoline ligand and the crystal structure analysis excludes the origin of π-π intermolecular interactions.     

Synthesis, spectroscopic characterization and structural studies of mixed ligand complexes of Sr(II) and Ba(II) with 2-hydroxybenzophenone and salicylaldehyde, hydroxyaromatic ketones or β-diketones: Crystal structure of 2-HOC6H4C(O)C6H5

Reactions of Sr(II) and Ba(II) chlorides with 2-hydroxybenzophenone and salicylaldehyde, hydroxyaromatic ketones or β-diketones in 1:1:1 molar ratios have resulted in the formation of mixed ligand complexes of the type [MLL′(H₂O)₂] (M = Sr(II) or Ba(II); HL = 2-hydroxybenzophenone and HL′ = salicylaldehyde, 2-hydroxyacetophenone, 2-hydroxypropiophenone, pentane-2,4-dione, 1-phenylbutane-1,3-dione or 1,3-diphenylpropane-1,3-dione). These complexes have been characterized by elemental analyses, TLC, IR and ¹H NMR spectroscopy.     

The Effects of Some Chelating Agents and Their Copper Complexes on Photosynthesis in Scenedesmus quadricauda

The effects on apparent photosynthesis in the green alga Scenedesmus quadricauda of four chelating substances, 8-hydroxyquinoline (= oxine), β-isopropyltropolone (=β-thujaplicin), sodium dimethyldithiocarbamate and 3-(β-hydroxyethyl)-C-pentamethylene-3-aza-dithiocarbamate have been investigated. The first three compounds mentioned had all an inhibitory effect on photosynthesis, measured as oxygen production with a manometric, a volumetric or a polarographic method. In combination with certain concentrations of CuSO₄ bimodal dose response curves were observed, similar to those obtained on the growth of different microorganisms. Calculations of the amounts of different complexes that appeared in the nutrient solutions during the experiments are compared with the recorded degrees of inhibition. The results strongly indicate that the 1: 1-complexes between Cu²⁺ and the chelating substances are the most toxic agents at low concentrations of these compounds.     

Five novel palladium(II) complexes of 8-hydroxyquinoline and amino acids with hydrophobic side chains: synthesis,characterization, cytotoxicity,DNA- and BSA-interaction studies

Abstract

The side effects and resistance of metal-based anticancer drugs prompted us to synthesis a novel series of five Pd(II) complexes of the type [Pd(8-QO)(AA)]; where 8-QO?=?anion of 8-hydroxyquinoline and AA?=?anions of amino acids having nonpolar aliphatic side chain such as glycine (–H), alanine (–CH₃), valine (–CH(CH₃)₂), leucine (–CH₂–CH(CH₃)₂) and isoleucine (–CH(CH₃)CH₂–CH₃). The complexes have been characterized with the help of FT-IR, UV–Vis, one and two-dimensional ¹H-NMR, elemental analysis and conductivity measurements. On the basis of these characterization data, a four coordinated square planar geometry for all of these complexes have been proposed. The compounds were screened for their in vitro activities against human cancer cell line, MOLT-4 and their 50% inhibition concentration were ascertained by means of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Since four out of the five newly synthesized compounds were found to be more active than the standard anticancer drug, cisplatin, their detailed interaction with calf thymus DNA (as a target) and bovine serum albumin (BSA) (as a carrier) were also carried out by utilizing absorption spectra, fluorescence spectra and ethidium bromide displacement studies. In these experiments, several binding and thermodynamic parameters were also calculated. These results suggested that hydrogen binding and van der Waals forces play a major role in the interaction between metal complexes with CT-DNA and BSA.

Communicated by Ramaswamy H. Sarma     

Structural characterization and electrochemical behavior of oxovanadium(V) complexes with N-salicylidene hydrazides

The hydrazone ligands derived from salicylaldehyde and aliphatic carbonic acid hydrazides react with equimolecular amounts of ammonium metavanadate and 8-hydroxyquinoline in refluxing methanol to yield oxovanadium(V) complexes. The synthesis can alternatively be performed starting from [VO(acac)₂] followed by aerial oxidation to form the corresponding oxovanadium(V) complexes. The molecular structures determined by X-ray crystallography feature in all cases a oxovanadium(V) moiety in an distorted octahedral arrangement with an oxygen and nitrogen rich environment. The obtained compounds posses very good solubility in organic solvents, permitting electrochemical investigation. Square wave voltammetric measurements revealed two reversible one-electron reduction steps at 0.355 and −1.638 V. The reduction of the oxovanadium(V) complexes to the corresponding vanadium(IV) species occurs at relatively positive potential, which is independently verified by ESR spectroscopy. While the second reduction step appears to be accompanied by a pre-wave exhibiting an unusual frequency dependence which can be attributed to ligand addition/elimination equilibria related to the 8-hydroxyquinoline coligand. The oxovanadium(V) complexes can be converted into the corresponding cis-dioxovanadium(V) compounds by reaction with aqueous NaOH. ⁵¹V NMR monitoring of this reaction reveals that one equivalent of base results in a full conversion with the cis-dioxovanadium(V) complex being the only species present in solution.     

A matrix-focused structure-activity and binding site flexibility study of quinolinol inhibitors of botulinum neurotoxin serotype A

Our initial discovery of 8-hydroxyquinoline inhibitors of BoNT/A and separation/testing of enantiomers of one of the more active leads indicated considerable flexibility in the binding site. We designed a limited study to investigate this flexibility and probe structure-activity relationships; utilizing the Betti reaction, a 36 compound matrix of quinolinol BoNT/A LC inhibitors was developed using three 8-hydroxyquinolines, three heteroaromatic amines, and four substituted benzaldehydes. This study has revealed some of the most effective quinolinol-based BoNT/A inhibitors to date, with 7 compounds displaying IC₅₀ values ?1 μM and 11 effective at ?2 μM in an ex vivo assay.     

Structure-activity relationships for inhibition of prostaglandin cyclooxygenase by phenolic compounds

Sixty-three phenolic compounds were examined for their ability to inhibit sheep vesicular gland prostaglandin cyclooxygenase. Examination of structure-activity relationships for these compounds indicated that inhibition was increased by ring substituents which were electron donating and by substituents which were hydrophobic. Inhibition was decreased by steric masking of the phenolic hydroxyl. The most potent inhibitors possessed a two aromatic ring structure connected by a short bridge. In these inhibitors, one ring was apolar, the other ring contained a phenolic hydroxyl ortho to the bridge, and the bridge contained a Lewis base such that the compounds could form bidentate metal chelates. Compounds with [I]₅₀ values of less than 10 uM included 2,4,6-trimethyl phenol, 7.2 uM; 2-(2-hydroxyphenyl)benzothiazole, 7.0 uM; 2-benzyloxyphenol, 5.2 uM; and 2-hydroxybenzophenone, 3.8 uM.Inhibition of arachidonate induced platelet aggregation was examined for three of the more potent inhibitors. 2-Benzyloxyphenol and 2,4,6-trimethylphenol were more potent than indomethacin when assayed using a 2 min preincubation of inhibitor with platelets.     

Optical and electrochemical properties and the calculated structure of pentacoordinate aluminum 8-hydroxyquinoline

In this study we report on the characterization of a series of pentacoordinate aluminum 8-hydroxyquinolines, AlQ₂X (X = F, Cl, Br), composed of two 8-hydroxyquinoline (8-HQ) groups and one halogen ligand. These were prepared by reacting 8-hydroxyquinoline and dialkylaluminum halide stoichiometrically. The λ_maxs of absorption and emission were in the range of 385-388 and 515-516 nm, respectively, which were similar to AlQ₃. The molar absorptivity of AlQ₂X is similar regardless of the X group but emission efficiency of AlQ₂X is 2-3 fold higher than that of AlQ₃ when X = F or Br, but not when X = Cl. This result can be attributed to decreased quenching of energy due to a less steric environment by reducing quinolinate content. The overall molecular orbital structures and the absorption spectra of AlQ₂X and AlQ₃ are very similar due to a single quinolinate unit. The value of the potential difference of AlQ₂Xs between anodic and cathodic waves (ΔE = 3.12 V) is close to the estimated HOMO-LUMO energy gap (the optical band gap, ΔE_optical ∼ 1240/λ_max), 3.19 eV. Detailed optical and electrochemical properties of AlQ₂X are discussed.     

Targeted 8-hydroxyquinoline fragment based small molecule drug discovery against neglected botulinum neurotoxin type F

ObjectivesBotulinum neurotoxins are highly potent biological warfare agents. The unavailability of countermeasures against these neurotoxins has been a matter of extensive research. However, no clinical therapeutics has come to existence till date. The 8-hydroxyquinoline (8-HQ) scaffold is established privileged compound and its potential as drug candidate against BoNTs is recently being explored.MethodsIn present work, three course studies were performed involving in silico, in vitro and in vivo cascade to screen 8-HQ small molecule inhibitors against BoNT/F intoxication. ~800 molecules obtained from open repositories were screened in silico and commercially obtained twenty-four 8-HQ derived small molecule inhibitors were evaluated against rBoNT/F light chain through fluorescence thermal shift (FTS) assay. Selected compounds were further evaluated through endopeptidase assay. Further binding affinity analysis was done through surface plasmon resonance (SPR) based Proteon™ XPR 36 system. Finally, the in vivo efficacy of these compounds was evaluated in mice model.ResultsThree compounds NSC1011, NSC1014 and NSC84094 were found to be highly inhibitory after screening of 8-HQ compounds through FTS assay and endopeptidase assay. SPR based protein-small molecule interaction studies showed highest affinity binding of NSC1014 (K_D: 5.58E-06) with BoNT/F-LC. NSC1011, NSC1014, and NSC84094 displayed IC₅₀ of 30.47 ± 6.24, 14.91 ± 2.49 and 17.39 ± 2.74 μM, respectively, in endopeptidase assay. NSC1011 and NSC1014 displayed marked extension of survival time in mice model.ConclusionNSC1011 and NSC1014 have emerged as promising drug candidate against BoNT/F intoxication displaying higher potential than previously reported compounds.     

Synthesis, characterization and preliminary insulin-enhancing studies of symmetrical tetradentate Schiff base complexes of oxovanadium(IV)

A series of oxovanadium(IV) symmetrical tetradentate Schiff base complexes have been isolated from the reaction of VOSO₄ with Schiff bases obtained from the condensation of 2-hydroxybenzophenone or 2-hydroxy-5-chlorosalicylaldehyde with various aliphatic diamines. The compounds were characterized by elemental analyses, ¹H NMR, infrared, electron paramagnetic resonance, electronic spectral, cyclic voltammetry and room temperature magnetic susceptibility measurements. The solution EPR spectra are consistent with square pyramidal complexes with C_4v symmetry. The IR spectra confirmed that the complexes are all monomeric except for [VO(Clsal)₂tn] which polymerizes via OV?VO linkages. The electronic spectra indicate a square pyramidal geometry in both non-coordinating and coordinating solvents except for [VO(bp₂-pn)] which appears to be octahedral in DMSO. The room temperature magnetic moments of 1.7-1.8 B.M. are normal for V(IV) d¹ configuration. Evidence for electrochemical pseudo-reversibility is presented for four of the complexes. In vitro studies revealed that two of the compounds, [VO(bp₂-en] and [VO(bp₂-tn)MeOH], significantly increased glucose uptake when compared to the basal glucose uptake in transformed and sensitized C1C12 cells, but not at the same level as insulin.     

Hepatocyte or serum albumin protein carbonylation by oxidized fructose metabolites: Glyceraldehyde or glycolaldehyde as endogenous toxins?

Excessive sugar intake in animal models may cause tissue damage associated with oxidative and carbonyl stress cytotoxicity as well as inflammation. Fructose became a 100-fold more cytotoxic if hepatocytes were exposed to a non-toxic infusion of H₂O₂ so as to simulate H₂O₂ released by Kupffer cells or infiltrating immune cells. In order to determine the molecular mechanisms involved, protein carbonylation of fructose and its metabolites were determined using the 2,4-dinitrophenylhydrazine method. In a cell-free system, fructose was found to carbonylate bovine serum albumin (BSA) only if low concentrations of FeII/H₂O₂ were added. Protein carbonylation by the fructose metabolites glyceraldehyde or glycolaldehyde was also markedly increased by FeII/H₂O₂. The protein carbonylation may be attributed to glyoxal formation by hydroxyl radicals as the glyoxal trapping agent aminoguanidine or hydroxyl radical scavengers prevented protein carbonylation. Glyoxal was also much more effective than other carbonyls at causing protein carbonylation. When BSA was replaced by isolated rat hepatocytes, fructose metabolite glyceraldehyde in the presence of non-toxic 2 μM FeII:8-hydroxyquinoline (HQ) and a H₂O₂ generating system (glucose/glucose oxidase) markedly increased cytotoxicity, protein carbonylation and reactive oxygen species (ROS)/H₂O₂ formation. Furthermore this was prevented by hydroxyl radical scavengers or aminoguanidine, a glyoxal scavenger. CuII: 8-hydroxyquinoline increased H₂O₂ induced hepatocyte protein carbonylation less but was prevented by aminoguanidine. However, cytotoxicity and protein carbonylation induced by glyceraldehyde/CuII:HQ/H₂O₂ were not affected by hydroxyl radical scavengers. Although fatty liver induced by an excessive sugar diet in animal models has been proposed as the first hit for non-alcoholic steatohepatitis (NASH) we propose that oxidative stress induced by the oxidation of fructose or fructose metabolites catalysed by Fenton FeII/H₂O₂ could be a ‘second hit’. A perpetual cycle of oxidative stress in hepatocytes could lead to cytotoxicity and contribute to NASH development.     

Novel 8-hydroxyquinoline derivatives targeting β-amyloid aggregation,metal chelation and oxidative stress against Alzheimer’s disease

A series of multitargeted 8-hydroxyquinoline derivatives were designed and synthesized for the treatment of Alzheimer’s disease (AD). In vitro studies indicated that most of the prepared compounds exhibited significant inhibitory effects against self-induced Aβ_1?42 aggregation and potential antioxidant properties especially compound 5b (IC₅₀?=?5.64?μM for self-induced Aβ aggregation; the oxygen radical absorbance capacity using fluorescein (ORAC-FL) value is 2.63 Trolox equivalents). Notably, 5b can chelate biometals and inhibit Cu²⁺/Zn²⁺-induced Aβ_1?42 aggregation. The cell assays showed that 5b had excellent protective effects against oxidative toxin H₂O₂ and presented low neurotoxicity in PC12 cells. Furthermore, 5b could penetrate the blood–brain barrier (BBB) in vitro and did not show any acute toxicity in mice at doses up to 2000?mg/kg in vivo. Our findings provide a rationale for the potential application of compound 5b as a lead compound in AD therapy.     

Efficient synthetic route to anhydrous mononuclear tris(8-quinolinolato)lanthanoid complexes for organic light-emitting devices

A new lanthanoid 8-quinilinolates type structure was found for lanthanum complex La₃(q^Me)₉(H)(NO₃) (1) formed in the reaction of La(NO₃)₃ · 6H₂O with 2-methyl-8-hydroxyquinoline (Hq^Me) and aqueous ammonia in methanol. The molecule of 1 contains three La atoms connected by six bridging quinolinolate ligands, two terminated η²-coordinated q^Me ligands, one terminated η¹-coordinated q^Me ligand and one terminated NO₃ group. The geometry and ¹H NMR spectrum of the complex suggest that it is bearing −1 charge balanced by proton, which was localized objectively. The arrangement of the compound in crystalline state and in pyridine solution is discussed. Syntheses of water- and acid residual-free mononuclear lanthanoid quinolinolates La(q^Me)₃(py)₂ (2) and Lnq₃(py)₂, (Ln = Y (3), La (4), Sm (5), Eu (6), Tb (7), Er (8), Tm (9); q = 8-quinolinolate, py = pyridine) by the reaction of appropriate amido complexes Ln[N(SMe₃)₂]₃ with 3 equiv. of 2-methyl-8-hydroxyquinoline or 8-hydroxyquinoline in pyridine solution is also described. The complex Laq₃(Ph₃PO)₂ (10) was prepared by treatment of 4 with triphenylphosphine oxide in pyridine solution. Lanthanum 2 complex revealed photoluminescence intensity ca. 3 × 10³ times higher than that of the compound 1 prepared by the traditional way in water-alcohol medium. These data give a ground to consider the Lnq₃(py)₂ complexes as promising material for design of light-emitting devices.     

Synthesis and evaluation of 1-(quinoliloxypropyl)-4-aryl piperazines for atypical antipsychotic effect

A series of 1-(quinoliloxypropyl)-4-aryl-piperazines has been synthesized and the target compounds evaluated for atypical antipsychotic activity in apomorphine induced mesh climbing and stereotypic behaviour in mice. The 8-hydroxyquinoline ether derivative 14 has emerged as an important lead compound showing a potential atypical antipsychotic profile. Employing appropriate physicochemical properties, the similarity of the compounds was assessed with respect to some atypical antipsychotic drugs as clozapine, ketanserine, ziprasidone and risperidone.     

8-hydroxyquinoline and quinazoline derivatives as potential new alternatives to combat Candida spp. biofilm

Often associated to the colonization by Candida spp. biofilm, the catheter-related infections are a serious health problem since the absence of a specific therapy. Hence, the main objective of this work was to evaluate the activity of 8-hydroxyquinoline and quinazoline derivatives on Candida spp. biofilms. A quinazoline derivative (PH100) and an 8-hydroxyquinoline derivative (PH157) were tested against nine strains of C. albicans, C. tropicalis and C. parapsilosis, and their biofilms in polystyrene microtitre plates and on polyurethane central venous catheter. The PH157 compound was incorporated into a film-forming system-type formulation and its capacity to inhibit biofilm formation on catheters was evaluated. The compounds were active against planktonic and sessile cells, as well as against the tested biofilms. PH157 compound performed better than the PH100 compound. The formulation containing PH157 presented results very similar to those of the compound in solution, which indicates that its activity was preserved. Both compounds showed activity against Candida spp. strains and their biofilm, with better PH157 activity. The formulation preserved the action of the PH157 compound, in addition, it facilitates its application on the catheter. The structural modifications that these compounds allow can generate compounds that are even more active, both against planktonic cells and biofilms.     

Diamine oxidase of Lathyrus sativus seedlings

A diamine oxidase has been purified (ca 40-fold) from 5-day old etiolated seedlings of L. sativus by MnCl₂ treatment, (NH₄)₂SO₄ and Me₂CO fractionations, positive adsorption on alumina Cγ-gel followed by column chromatography on DEAE-Sephadex. This cytosol enzyme oxidatively deaminates a number of aliphatic and aryl alkylamines but not histamine. NSD-1055, semicarbazide and other carbonyl reagents, α,α'bipyridyl, 1,10-phenanthroline and 8-hydroxyquinoline inhibit the enzyme. Pargyline, SKF trans-385, atabrine were without effect on the enzyme.     

Light-dependent reduction of hydrogen peroxide by ruptured pea chloroplasts

Ruptured pea (Pisum sativum cv. Massey Gem) chloroplasts exhibited ascorbate peroxidase activity as determined by H₂O₂-dependent oxidation of ascorbate and ascorbate-dependent reduction of H₂O₂. The ratio of ascorbate peroxidase to NADP-glyceraldehyde 3-phosphate dehydrogenase activity was constant during repeated washing of isolated chloroplasts. This indicates that the ascorbate peroxidase is a chloroplast enzyme. The pH optimum of ascorbate peroxidase activity was 8.2 and the K_m value for ascorbate was 0.6 millimolar. Pyrogallol, glutathione, and NAD(P)H did not substitute for ascorbate in the enzyme catalyzed reaction. The enzyme was inhibited by NaN₃, KCN, and 8-hydroxyquinoline but not ZnCl₂ or iodoacetate. The ascorbate peroxidase activity of sonicated chloroplasts was inhibited by light but not in the presence of substrate concentrations of ascorbate.     

An improved chromosome preparation from male gametophyte of Laminaria japonica (Heterokontophyta)

An improved method for the preparation of chromosomes from the male gametophyte of the alga Laminaria japonica Aresch. was described. The male gametophyte was pretreated with pDB (p-dichlorobenzene) and 8-hydroxyquinoline in order to clear cell wall and soften cytoplasm. The samples were treated by mordant iron alum [FeNH₄ (SO₄)₂⋅6H₂O] followed by staining with haemotoxylin. Well-spread and highly stained chromosomes were observed without precipitation. The chromosome number of male gametophyte of L. japonica was estimated to be 31. %