8-hydroxyquinoline Derivatives Research Articles

Antifungal activity of azoles, allylamines, and 8-hidroxiquinolines, alone and in combination, against Malassezia pachydermatis in vitro and in vivo

Malassezia pachydermatis is often reported as the causative agent of dermatitis in dogs. This study aims to evaluate the in vitro and in vivo antifungal activity of azoles and terbinafine (TRB), alone and in combination with the 8-hydroxyquinoline derivatives (8-HQs) clioquinol (CQL), 8-hydroxyquinoline-5-(n-4-chlorophenyl)sulfonamide (PH151), and 8-hydroxyquinoline-5-(n-4-methoxyphenyl)sulfonamide (PH153), against 16 M. pachydermatis isolates. Susceptibility to the drugs was evaluated by in vitro broth microdilution and time-kill assays. The Toll-deficient Drosophila melanogaster fly model was used to assess the efficacy of drugs in vivo. In vitro tests showed that ketoconazole (KTZ) was the most active drug, followed by TRB and CQL. The combinations itraconazole (ITZ)+CQL and ITZ+PH151 resulted in the highest percentages of synergism and none of the combinations resulted in antagonism. TRB showed the highest survival rates after seven days of treatment of the flies, followed by CQL and ITZ, whereas the evaluation of fungal burden of dead flies showed a greater fungicidal effect of azoles when compared to the other drugs. Here we showed for the first time that CQL is effective against M. pachydermatis and potentially interesting for the treatment of malasseziosis.

The 8-hydroxyquinoline derivative, clioquinol, is an alpha-1 adrenoceptor antagonist

Clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) is an antimicrobial agent whose actions as a zinc or copper ionophore and an iron chelator revived the interest in similar compounds for the treatment of fungal and bacterial infections, neurodegeneration and cancer. Recently, we reported zinc ionophores, including clioquinol, cause vasorelaxation in isolated arteries through mechanisms that involve sensory nerves, endothelium and vascular smooth muscle. Here, we report that clioquinol also uniquely acts as a competitive alpha-1 (α1) adrenoceptor antagonist. We employed ex vivo functional vascular contraction and pharmacological techniques in rat isolated mesenteric arteries, receptor binding assays using stabilized solubilized α1 receptor variants, or wild-type human α1-adrenoceptors transfected in COS-7 cells (African green monkey kidney fibroblast-like cells), and molecular dynamics homology modelling based on the recently published α1A adrenoceptor cryo-EM and α1B crystal structures. At higher concentrations, all ionophores including clioquinol cause a non-competitive antagonism of agonist-mediated contraction due to intracellular zinc delivery, as reported previously. However, at lower concentration ranges, clioquinol has an additional mechanism of competitively inhibiting α1-adrenoceptors that contributes to decreasing vascular contractility. Molecular dynamic simulation showed that clioquinol binds stably to the orthosteric binding site (Asp106) of the receptor, confirming the structural basis for competitive α1-adrenoceptor antagonism by clioquinol.

Deciphering neuroprotective mechanism of nitroxoline in cerebral ischemia: network pharmacology and molecular modeling-based investigations.

Cerebral ischemia is one of the major causes of death and disability worldwide. Currently, existing approved therapies are based on reperfusion and there is an unmet need to search for drugs with neuroprotective effects. The present study aims to investigate the neuroprotective mechanisms of nitroxoline, a nitro derivative of 8-Hydroxyquinoline, against cerebral ischemia using integrated network pharmacology and molecular docking approaches. Critical analytical tools used were SwissTarget, PharmMapper, BindingDB, DisGeNet, Cytoscape, GeneMANIA, ShinyGo, Metascape, GeneCodis, and Schrodinger GLIDE. Thirty-six overlapping drug and disease targets were identified and used for further analysis. Gene Ontology results showed that nitroxoline enriched the genes involved in biological processes of oxidative stress and apoptotic cell death that are highly implicated in hypoxic injury. KEGG enrichment analysis showed nitroxoline influenced a total of 159 biological pathways, out of which, top pathways involved in cerebral ischemia included longevity regulating pathway, VEGF signaling, EGFR tyrosine kinase inhibitor resistance, IL-17 and HIF-1 pathways, FoxO signaling, and AGE-RAGE pathway. Protein-protein interaction analysis using string database showed PARP1, EGFR, PTEN, BRD4, RAC1, NOS2, MTOR, MAPK3, BCL2, MAPK1, APP, METAP2, MAPK14, SIRT1, PRKAA1, and MCL1 as highly interactive proteins involved in pathogenesis of ischemic stroke regulated by nitroxoline. The highly interactive protein targets were validated by molecular docking studies and molecular dynamic simulations. Amongst all these targets, nitroxoline showed the highest binding affinity towards BRD4 followed by PARP1 and PTEN.Nitroxoline, through network pharmacology analysis, showed a role in regulating proteins, biological processes, and pathways crucial in cerebral ischemia. The current study thus provides a preliminary insight that nitroxoline might be used as a neuroprotectant against cerebral ischemia via modulating the epigenetic reader BRD4 and transcription factors such as RELA, NF-κβ1, and SP1. However, further in-vitro and preclinical studies need to be performed for concrete evidence.

Facing diseases caused by trypanosomatid parasites: rational design of multifunctional oxidovanadium(IV) complexes with bioactive ligands

Searching for new prospective drugs against Chagas disease (American trypanosomiasis) and Leishmaniasis, a series of five heteroleptic vanadium compounds, [VIVO(L-H)(mpo)], where L are 8-hydroxyquinoline derivatives and mpo is 2-mercaptopyridine N-oxide, are synthesized and characterized. Comprehensive characterizations are conducted in solid state and in solution. The compounds are evaluated on epimastigotes and trypomastigotes of Trypanosoma cruzi and in promastigotes of Leishmania infantum, alongside on VERO cells, as a mammalian cell model. The compounds exhibit activity against both forms of T. cruzi and promastigotes of L. infantum, with the trypomastigote infective stage of T. cruzi displaying the highest sensitivity. The most selective vanadium compound [VIVO(L2-H)(mpo)], with L2 = 5-chloro-7-iodo-8-hydroxyquinoline, globally shows adequate selectivity towards the parasite and was selected to carry out further in-depth biological studies. [VIVO(L2-H)(mpo)] significantly impacted the infection potential of cell-derived trypomastigotes and hindered the replication of the T. cruzi amastigote form. Low total vanadium uptake by T. cruzi parasites and preferential accumulation in the soluble proteins fraction, with negligible localization in the DNA fraction, are determined. A trypanocide effect is observed across various concentrations of the compound. The generation of oxidative stress and the induction of mitochondria-dependent apoptosis are proposed as the main mechanisms of the parasite’s death by the VIVO compounds. Both theoretical predictions and experimental data support the hypothesis that inhibiting the parasite-specific enzyme NADH-fumarate reductase activity plays a crucial role in the trypanocidal action of these complexes. Globally, [VIVO(L-H)(mpo)] complexes could be considered interesting anti-T. cruzi agents that deserve further research.

Oxidant-Dependent Sensitizing, Protective, and Mitigative Effects in X-Ray-Irradiated Pulmonary Endothelial Cells.

The primary response of proliferating bovine pulmonary artery endothelial cells (BPAECs) after X-ray irradiation [≤10 gray (Gy)] is shown to be transient cell-cycle arrest. Accompanying oxidant-linked functional changes within the mitochondria are readily measured, but increased autophagy is not. Radiation-induced apoptosis is negligible in this line-important because cells undergoing apoptosis release oxygen-derived species that can overwhelm/mask the radiation-associated species and their effects that we wish to investigate. Cells irradiated and cultured at 3% oxygen exhibited delayed cell-cycle arrest (6-8 hours after 10 Gy irradiation) compared with those maintained at 20% oxygen (2-4 hours after 10 Gy irradiation). At 3% oxygen, either only during or only after irradiation, results intermediate between 20% and 3% oxygen throughout were obtained. No variability in cell-cycle distribution was observed for unirradiated cells cultured under different prevailing oxygen levels. Mitochondrially localized manganese superoxide dismutase delayed the X-ray-induced cell-cycle changes when over-expressed in BPAEC, indicating superoxide to be one of the key oxygen-derived cytotoxic species involved in the radiobiological response. Also, the peroxynitrite biomarker 3-nitrotyrosine was elevated, whereas hydrogen peroxide levels were not. Lastly, the utility of the BPAEC for screening potential countermeasures to ionizing radiation is demonstrated with some quinoline derivatives. Three of the five compounds appeared mitigative, and all were protective. It is suggested that the oxidation-reduction chemistry of these compounds probably offers a reasonable explanation for their observed ameliorative properties. Furthermore, the results suggest a promising new direction in the search for lead compounds as countermeasures to the effects of ionizing radiation. SIGNIFICANCE STATEMENT: The primary radiological response of proliferating bovine pulmonary artery endothelial cells is cell-cycle arrest, starting soon after X-ray irradiation (1-10 Gy) at 20% O2 but delayed by 4 hours at systemic (3%) O2. Oxygen/superoxide is found to be radio-sensitizing in at least two distinct time windows, during and after the irradiation, with both responses antagonized by various hydroxyquinoline derivatives. Similar responses in many other cell lines are likely to be masked by elevated oxidants associated with apoptosis.

New type of tin(IV) complex based turn-on fluorescent chemosensor for fluoride ion recognition: elucidating the effect of molecular structure on sensing property.

A novel type of chemosensor based on tin(IV) complexes incorporating hydroxyquinoline derivatives has been designed and investigated for selectively detecting fluoride ions. Sn(meq)2Cl2 (meq = 2-methyl-8-quinolinol) (complex 1) exhibits a significant enhancement in luminescence upon the introduction of fluoride ions. This enhancement greatly surpasses that observed with Snq2Cl2 and Sn(dmqo)2Cl2 (q = 8-hydroxyquinnoline; dmqo = 5,7-dimethyl-8-quinolinol). Furthermore, complex 1 displays excellent sensitivity and selectivity for fluoride detection in comparison to halides and other anions. As a result, complex 1 serves as an outstanding turn-on fluorescent chemosensor, effectively sensing fluoride ions. The Benesi-Hilderbrand method and Job's plot confirmed that complex 1 associates with F- in a 1 : 2 binding stoichiometry. Also, complex 1 exhibited a large binding constant (pKb = 10.4 M-2) and a low detection limit (100 nM). To gain a deeper insight into the photophysical properties and the underlying mechanism governing the formation of the tin(IV) fluoride complex via halide exchange, we successfully synthesized partially fluorinated Sn(meq)2F0.67Cl1.33 (2) and fully fluorinated Sn(meq)2F2 (3), all of which were characterized through computational studies, thereby elucidating their photophysical properties. DFT studies reveal that converting Sn(meq)2Cl2 to Sn(meq)2F2, an endergonic process, leads to greater stability due to reducing steric hindrance about the metal center. Furthermore, the fluorinated complex significantly increases dipole moment, resulting in high affinity toward the F- ion.

Discovery of Novel 8-Hydroxyquinoline Derivatives with Potent In Vitro and In Vivo Antifungal Activity.

Fungal pathogens can cause life-threatening infections, yet current antifungals are inadequate at treating many of these, highlighting the importance of novel drug discovery. Here, we report hit compound L14, a novel 8-hydroxyquinoline derivative with potent and broad-spectrum antifungal activity. In vitro experiments exhibited that L14 had better activity and lower cytotoxicity than that of clioquinol and showed synergy in combination with fluconazole (FLC). In a Candida albicans-infected murine model, L14 at 2 mg/kg showed better in vivo efficacy than clioquinol at reducing fungal burden and extending the survival of C. albicans-infected mice. In addition, L14 alone or in combination with FLC had significant inhibitory activity against hypha and biofilm formation. Overall, our data indicated that 8-hydroxyquinoline derivative L14 has favorable pharmacokinetics and acceptable safety profiles and could be further investigated as a promising antifungal hit compound.

In vitro evaluation of the efficacy of 8-hydroxyquinoline derivatives for the control of Phaeomoniella chlamydospora, the causative agent of Petri disease in grapevines.

This study evaluates the in vitro efficacy of 8-hydroxyquinoline (8HQ) derivatives in controlling the phytopathogenic fungus Phaeomoniella chlamydospora. The in vitro tests assessed the susceptibility to the minimum inhibitory concentration (MIC), checkerboard assay, mycelial growth (MG) inhibition, and EC50 determination. Among the seven agricultural fungicides tested, tebuconazole (TEB) displayed the lowest MIC, 1.01µg mL-1, followed by captan (CAP), thiophanate methyl (TM), and mancozeb with MICs of 4.06, 5.46, and 10.62µg mL-1, respectively. The 8HQ derivatives used in this study were clioquinol and PH 151 (PH) with MICs of 1.09 and 2.02µg mL-1, respectively. PH associated with TEB and CAP showed synergism and inhibited 95.8% of MG at the highest dose. TEB inhibited 100% of MG at the three highest doses, while associated with PH exhibited the lowest EC50 (0.863+0.0381µg mL-1). We concluded that the 8HQ derivatives tested controlled effectively the P. chlamydospora in vitro. PH associated with CAP and TEB exhibited a synergistic effect. The association between PH and TM was considered indifferent. This study expands the list of active ingredients tested against P. chlamydospora, with the PH 151 and clioquinol derivatives being tested for the first time. The in vitro efficacy and synergistic action with other fungicides suggest a potential use as a grapevine wound protectant. This association makes it possible to reduce doses and increase the potency of both drugs, reducing the risk of resistance development and harm to humans and the environment.

Three pseudo-dimeric lead halide complexes containing derivatives of 8-hydroxyquinoline, Cl2QPbX (X = Br, I), (Cl2Q)4Pb2:Synthesis, crystal structures, and fluorescence spectroscopic properties

Three new complexes, namely (5,7-Dichloro-8-hydroxyquinoline)PbX (X=Br, I) (1, 2) and Pb2(5,7-Dichloro-8-hydroxyquinoline)4 (3), were synthesized through solvent evaporation at ambient temperature. The crystal structures and fluorescence emission properties of these complexes were systematically investigated. An analysis using single crystal X-ray diffraction revealed that complexes 1-3 form pseudo-dimeric structures through the interaction between lead and neighboring oxygen via secondary contacts. A comparison between the structures of complex 2 and [Pb(μ-Q)I]2, a complex of PbI2 with 8-hydroxyquinoline, showed that the coordination polyhedron changed from a triangular pyramid to a distorted tetrahedron. This change may be attributed to the site resistance effect of the chlorine substituents coordinated to the quinoline ring. Complex 3 has a layered structure formed through secondary contacts and intramolecular hydrogen bonding C-H⋯O and C-H⋯Cl among the lamellar molecules. The maximum emission peak at 489 nm, 505 nm, and 543 nm for complex 1-3 can be assigned to the ligand-to-metal charge transfer (LMCT). The maximum emission peaks were red-shifted by 22 nm, 38 nm, and 75 nm, respectively, compared to the ligand. The number of ligands increases the conformational rigidity of the structure and the electron density on lead atoms causing the molecular structure to change, the energy alters, and the fluorescence peaks to move in the long-wave direction.

Pythium insidiosum: insights into biofilm formation and antibiofilm activity of antifungal drugs.

In this study, we investigate the ability of Pythium insidiosum to form biofilms across various substrates and the antibiofilm efficacy of 8-hydroxyquinoline derivatives (8-HQs). Biofilms of P. insidiosum were cultured on polystyrene plates, contact lenses, and horsehair. We provide the first evidence of P. insidiosum's biofilm-forming capability, thus considerably expanding our understanding of its transmission and pathogenesis. Our results demonstrate that 8-HQs effectively inhibit biofilm formation and eradicate pre-existing biofilms, underscoring their potential as a novel treatment strategy for pythiosis, a disease currently lacking a gold-standard treatment. This finding has particular relevance for ocular pythiosis associated with contact lens usage and potential infection sources in animals. Our results contribute to the scientific knowledge base and directly impact innovative therapeutic interventions' development.

Electrospun Fibers of Biocompatible and Biodegradable Polyesters, Poly(Ethylene Oxide) and Beeswax with Anti-Bacterial and Anti-Fungal Activities

Fibrous materials composed of core–sheath fibers from poly(ethylene oxide) (PEO), beeswax (BW) and 5-nitro-8-hydroxyquinoline (NQ) were prepared via the self-organization of PEO and BW during the single-spinneret electrospinning of a homogeneous blend solution of the partners. Additionally, the application of the same approach enabled the preparation of fibrous materials composed of core–double sheath fibers from PEO, poly(L-lactide) (PLA) and NQ or 5-chloro-7-iodo-8-hydroxyquinoline (CQ), as well as from PEO, poly(ε-caprolactone) (PCL) and NQ. The consecutive selective extraction of BW and of the polyester with hexane and tetrahydrofuran, respectively, evidenced that core–double sheath fibers from PEO/polyester/BW/drug consisted of a PEO core, a polyester inner sheath and a BW outer sheath. In order to evaluate the possibility of the application of fibrous materials from PEO/BW/NQ, PEO/PLA/BW/NQ, PEO/PCL/BW/NQ and PEO/PLA/BW/CQ for plant protection, microbiological studies were performed using both phytopathogenic microorganisms (Pseudomonas corrugata, Fusarium graminearum and Fusarium avenaceum) and beneficial microorganisms (Pseudomonas chlororaphis, Bacillus amyloliquefaciens and Trichoderma asperellum). It was found that the fibrous materials had anti-bacterial and anti-fungal activity against both phytopathogenic and beneficial microorganisms. This is the first report on the activity of fibrous materials loaded with 8-hydroxyquinoline derivatives not only against phytopathogenic but also against beneficial microorganisms that are of importance in agriculture.

Design, characteristics, and theoretical analyses of 8-hydroxyquinoline derivatives with different heteroatoms as effective corrosion inhibitors

This study focuses on the corrosion inhibition of N80 steel by 8-hydroxyquinoline derivatives in 1 M hydrochloric acid medium. Firstly, three corrosion inhibitors containing different heteroatoms, namely N-dodecyl-5-amino-methyl-8-hydroxyquinoline (12N-HQ), 5-dodecyloxy-methyl-8-hydroxyquinoline (12O-HQ), and 5-dodecylthio-methyl-8-hydroxyquinoline (12S-HQ) were synthesized from 1-dodecylamine, 1-dodecanol, 1-dodecanethiol, and 8-hydroxyquinoline. The structures of the synthesized products were characterized by infrared spectroscopy and nuclear magnetic resonance hydrogen spectrometry. The effects of 12N-HQ, 12O-HQ, and 12S-HQ on the corrosion of N80 steel in hydrochloric acid solution were studied by electrochemical measurements: electrochemical impedance spectroscopy (EIS) and potentiodynamic polarization (PDP). The surface analysis of N80 steel was carried out using infrared spectroscopy (FT-IR), scanning electron microscopy (FE-SEM), and X-ray diffractometer (XRD). The IR and 1HNMR spectra results confirmed the generation of characteristic peaks of C-N-C, C-O-C, and C-S-C, indicating that the products were 12N-HQ, 12O-HQ, and 12S-HQ. The PDP results demonstrated that the 12N-HQ, 12O-HQ, and 12S-HQ corrosion inhibitors were all mixed corrosion inhibitors. The EIS results were 93.60%, 93.37%, and 95.31% corrosion inhibition efficiency for the three inhibitors at a concentration of 1 mM, respectively. The FT-IR, FE-SEM, and XRD studies showed that 12N-HQ, 12O-HQ, and 12S-HQ molecules adhered and constructed a surface protective layer on the surface of N80 steel. Density flooding theory (DFT) calculations and molecular dynamics simulations (MD) better explain the influence of 12N-HQ, 12O-HQ, and 12S-HQ molecular structures and electrons on corrosion resistance, in addition to the results obtained by DFT and the simulation of MD agree with the experimental results.

Metal‐Free Synthesis of Pyrimidine and Naphthoquinone‐Fused Pyrroles from Arylglyoxal‐Based Domino Reactions

AbstractHerein we report acid mediated two and three‐component domino reactions of cyclic enamines such as 2‐amino‐1,4‐naphthoquinone, and 6‐amino‐1,3‐dimethyluracil with arylglyoxals for the synthesis of diverse fused pyrroles. The two‐component reaction of arylglyoxal and 2‐amino‐1,4‐naphthoquinone in the acetic acid medium provided substituted naphthoquinone‐fused pyrroles tethered with hydroxyl and aryl substituents. On the other hand, under similar reaction conditions, the reaction of phenylglyoxal with 6‐amino‐1,3‐dimethyluracil provided an unusual bipyrrolopyrimidine with a quaternary carbon center following a domino reaction involving the formation of five new sigma bonds in one‐pot. Interestingly, the reaction of arylglyoxals with 6‐amino‐1,3‐dimethyluracil in ethanol medium in the presence of 10‐mol% PTSA provided a three‐component product having pyrimidine fused pyrrole linked with 6‐aminouracil moiety. We have also developed a three‐component reaction of 2‐amino‐1,4‐naphthoquinone, arylglyoxals, and 4‐hydroxy‐1‐methylquinolin‐2(1H)‐one for the synthesis of naphthoquinone‐fused pyrroles linked with hydroxyquinoline derivatives.

Synthesis, Characterization and Biological Activity of Metal Chelates Based On 8-Hydroxyquinoline and 1, 2, 4-Triazol

The present study aims to synthesize a novel ligand namely, 5-((3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)methyl)-8-Hydroxyquinoline (TFMTHQ) by reacting 5-chloromethyl-8-hydroxyquinoline (CMQ) hydrochloride, a versatile derivative of 8-hydroxyquinoline with 3-trifluoromethyl-1-H-1,2,4-triazole. The co-ordinate metal chelates of the ligand TFMTHQ were prepared using divalent metal ions viz., Cu2+, Co2+, Ni2+, Mn2+, Zn2+ and Cd2+ by a simple method. The ligand TFMTHQ and its all metal chelates were duly characterized for elemental content, spectral features, M: L (metal: ligand) ratio, and magnetic moment. The results of electronic spectral studies and magnetic properties indicated octahedral geometry for all the metal chelates. All the synthesized compounds were tested for antibacterial activity against gram positive and gram negative bacteria. Antifungal activity of all the samples was tested against plant pathogens such as Aspergillus Niger (AN), Botrydepladia Thiobromine (BT), Nigrospora Sp. (NS), and Fusarium Oxyporium (FO). The results showed good antimicrobial activity of all the metal chelates.

Low-Dimensional Compounds Containing Bioactive Ligands. Part XX: Crystal Structures, Cytotoxic, Antimicrobial Activities and DNA/BSA Binding of Oligonuclear Zinc Complexes with Halogen Derivatives of 8-Hydroxyquinoline

Two tetranuclear [Zn4Cl2(ClQ)6]·2DMF (1) and [Zn4Cl2(ClQ)6(H2O)2]·4DMF (2), as well as three dinuclear [Zn2(ClQ)3(HClQ)3]I3 (3), [Zn2(dClQ)2(H2O)6(SO4)] (4) and [Zn2(dBrQ)2(H2O)6(SO4)] (5), complexes (HClQ = 5-chloro-8-hydroxyquinoline, HdClQ = 5,7-dichloro-8-hydroxyquinoline and HdBrQ = 5,7-dibromo-8-hydroxyquinoline) were prepared as possible anticancer or antimicrobial agents and characterized by IR spectroscopy, elemental analysis and single crystal X-ray structure analysis. The stability of the complexes in solution was verified by NMR spectroscopy. Antiproliferative activity and selectivity of the prepared complexes were studied using in vitro MTT assay against the HeLa, A549, MCF-7, MDA-MB-231, HCT116 and Caco-2 cancer cell lines and on the Cos-7 non-cancerous cell line. The most sensitive to the tested complexes was Caco-2 cell line. Among the tested complexes, complex 3 showed the highest cytotoxicity against all cell lines. Unfortunately, all complexes showed only poor selectivity to normal cells, except for complex 5, which showed a certain level of selectivity. Antibacterial potential was observed for complex 5 only. Moreover, the DNA/BSA binding potential of complexes 1–3 was investigated by UV-vis and fluorescence spectroscopic methods.

8-Hydroxyquinoline derivatives suppress GLI1-mediated transcription through multiple mechanisms

Aberrant activation of the Hedgehog (Hh) signaling pathway has been observed in various human malignancies. Glioma-associated oncogene transcription factor 1 (GLI1) is the ultimate effector of the canonical Hh pathway and has also been identified as a common regulator of several tumorigenic pathways prevalent in Hh-independent cancers. The anti-cancer potential of GLI1 antagonism with small molecule inhibitors has demonstrated initial promise; however, the continued development of GLI1 inhibitors is still needed. We previously identified a scaffold containing an 8-hydroxyquinoline as a promising lead GLI1 inhibitor (compound 1). To further develop this scaffold, we performed a systematic structure–activity relationship study to map the structural requirements of GLI1 inhibition by this chemotype. A series of biophysical and cellular experiments identified compound 39 as an enhanced GLI1 inhibitor with improved activity. In addition, our studies on this scaffold suggest a potential role for SRC family kinases in regulating oncogenic GLI1 transcriptional activity.

Synthesis, Characterization and Antifungal Activity of Metal Chelates Based on 8-Hydroxyquinoline and Metronidazole

In the present study, 5-chloromethyl-8-hydroxyquinoline (CMQ) hydrochloride, a versatile derivative of 8-hydroxyquinoline is reacted with a potent antibiotic drug metronidazole in order to yield a novel ligand namely 5-((2-(2-methyl-5-nitro-1H-imidazol-1-yl) ethoxy) methyl)-8-hydroxyquinoline (NIHQ). The co-ordinate metal chelates of the ligand NIHQ were prepared using divalent metal ions viz., Cu2+, Co2+, Ni2+, Mn2+, Zn2+ and Cd2+ by simple method. The ligand NIHQ and its all metal chelates were duly characterized for elemental content, spectral features, M: L (metal: ligand) ratio, and magnetic moment. The results of electronic spectral studies and magnetic properties indicated octahedral geometry for all the metal chelates. Antifungal activity of all the samples was tested against plant pathogens such as Aspergillus niger, Botrydepladia thiobromine, Nigrospora Sp., and Fusarium oxyporium. The results showed promising antifungal activity of all the metal chelates.

ХЕЛАТУВАННЯ ДВОВАЛЕНТНИХ КАТІОНІВ ТА АНТИРАКОВА АКТИВНІСТЬПОХІДНИХ 8-ГІДРОКСИСТИРИЛХІНОЛІНІВ IN VITRO

Background. The search for new methods of cancer treatment and diagnosis are important. The disadvantages of chemotherapy drugs are the rapid acquisition of resistance and high toxicity. 8-hydroxyquinoline derivatives have a wide spectrum of biological activity and have the necessary properties for fluorescent cancer diagnosis. The aim of the study was to determine the chelation of calcium, magnesium and zinc cations by hydrophobic derivatives of 8-hydroxystyrylquinolines (8HQ) 2-(4-chlorostyryl)quinolin-8-ol (STQ-Cl) and 2-(4-nitrostyryl)quinolin-8-ol (STQ-NO2) in physiological solution, the stability of the complexes and the cytotoxicity of the compounds to prostate and breast cancer cell lines in vitro. Methods. 8HQ derivatives STQ-Cl and STQ-NO2 were used. Solutions of Ca2+, Mg2+, Zn2+ cations were prepared by the method of two-fold dilutions in 0.5-0.0078125 mM concentration range based on 0.9 % NaCl. Both individual solutions of each cation and a mixture in an equivalent molar ratio were used. The concentration of 8HQ derivatives were 0.05 mM. Optical absorption was registered in 200-700 nm wavelength range. Cytotoxicity was investigated on breast (MDA-MB-231) and prostate (DU-145) cancer cell lines. STQ-Cl and STQ-NO2 derivatives in DMSO were added to the incubation solution by four-fold dilutions (0.125–0.00003 mM). For luminescence studies, MDA-MB-231 and DU-145 cells were grown on coverslips. The final concentration of 8HQ derivatives were 5 mM. Cells were kept for 5, 10, 20 and 30 min. Luminescence was recorded under the same conditions for all samples, with an exposure time of 10 ms. Results. Mg2+ and Ca2+ (0.03125 mM) were contributed to reduce the intensity of optical absorption maxima of STQ-Cl by 1.6 and 1.3 times, respectively. The effect was most pronounced at 0.015625 mM Zn2+. Weak differences in the optical absorption of solutions were detected when STQ-NO2 was incubated with different concentrations of Mg2+ and Ca2+. The optical absorption intensity of the STQ-NO2 aqueous solution was increased at 0.015625 and 0.03125 mM Zn2+. The maximum cytotoxicity against MDA-MB-231 cells for STQ-Cl was about 80 %, and STQ-NO2 was 60 % at 0.04 mM Zn2+. DU-145 cells were more sensitive to STQ-NO2 (EC50 = 0.011 mM), but weakly sensitive to STQ-Cl (50 % at 0.125 mM). The maximum luminescence intensity was after 20 min of incubation with STQ-Cl and STQ-NO2 (5 mM) for both cells lines and was not change over time. Conclusions. The decrease of optical absorption maxima of STQ-Cl aqueous solutions in the presence of magnesium, calcium, and zinc cations was a consequence of aggregation processes. This phenomenon was probably the reason for the different cytotoxicity of STQ-Cl and STQ-NO2, as well as the presence of other mechanisms of action to cancer cells. Results was a consequence of different affinity of 8-hydroxyquinoline derivatives to magnesium, calcium and zinc cations, solubility in water, stability, aggregation of metal complexes and free compounds.

Anti-Biocorrosive and Biocidal Efficacy of Hydroxyquinoline Derivative as Seawater Corrosion Inhibitor

Anti-Biocorrosive and Biocidal Efficacy of Hydroxyquinoline Derivative as Seawater Corrosion Inhibitor

PhI(OAc)2/Pd(OAc)2 promoted the formation of 8-hydroxyquinoline derivatives from benzoxazoles and alcohols.

A PhI(OAc)2/Pd(OAc)2 system that synergistically promotes the formation of 8-hydroxyquinoline derivatives from benzoxazoles and alcohols has been developed. The reaction proceeded smoothly with a range of benzoxazoles and alcohols to give the corresponding 8-hydroxyquinoline derivatives in moderate yields.