Cardiotoxicity and ROS Protection Assessment of three Structure-Related N-Acylhydrazones with Potential for the Treatment of Neurodegenerative Diseases.

The senescence process is associated with accumulated oxidative damage and increased metal concentration in the heart and brain. Besides, abnormal metal-protein interactions have also been linked with the development of several conditions, including Alzheimer's and Parkinson's diseases. Over the years we have described a series of structure-related compounds with different activities towards models of such diseases. In this work, we evaluated the potential of three N-acylhydrazones (INHHQ: 8-hydroxyquinoline-2-carboxaldehyde isonicotinoyl hydrazone, HPCIH: pyridine-2-carboxaldehyde isonicotinoyl hydrazone and X1INH: 1-methyl-1H-imidazole-2-carboxaldehyde isonicotinoyl hydrazone) to prevent oxidative stress in cellular models, with the dual intent of being active on this pathway and also to confirm their lack of cardiotoxicity as an important step in the drug development process, especially considering that the target population often presents cardiovascular comorbidity. The 8-hydroxyquinoline-contaning compound, INHHQ, exhibits a significant cardioprotective effect against hydrogen peroxide and a robust antioxidant activity. However, this compound is the most toxic to the studied cell models and seems to induce oxidative damage on its own. Interestingly, although not possessing a phenol group in its structure, the new-generation 1-methylimidazole derivative X1INH showed a cardioprotective tendency towards H9c2 cells, demonstrating the importance of attaining a compromise between activity and intrinsic cytotoxicity when developing a drug candidate.

Synthesis, characterization, and cancer cell-selective cytotoxicity of mixed-ligand cobalt(III) complexes of 8-hydroxyquinolines and phenanthroline bases.

Transition metal complexes exhibiting selective toxicity towards a broad range of cancer types are highly desirable as potential anticancer agents. Herein, we report the synthesis, characterization, and cytotoxicity studies of six new mixed-ligand cobalt(III) complexes of general formula [Co(B)2(L)](ClO4)2 (1-6), where B is a N,N-donor phenanthroline base, namely, 1,10-phenanthroline (phen in 1, 2), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq in 3, 4), and dipyrido[3,2-a:2',3'-c]phenazine (dppz in 5, 6), and L is the monoanion of 8-hydroxyquinoline (HQ in 1, 3, 5) and 5-chloro-7-iodo-8-hydroxyquinoline (CQ in 2, 4, 6). The X-ray single crystal structures of complexes 1 and 2 as PF6- salts revealed a distorted octahedral CoN5O coordination environment. Complexes demonstrated good stability in an aqueous buffer medium and in the presence of ascorbic acid as a reductant. Cytotoxicity studies using a panel of nine cancer cell lines showed that complex 6, with the dppz and CQ ligands, was significantly toxic against most cancer cell types, yielding IC50 values in the range of 2 to 14 µM. Complexes 1, 3, and 5, containing the HQ ligand, displayed lower toxicity compared to their CQ counterparts. The phenanthroline complexes demonstrated marginal toxicity towards the tested cell lines, while the dpq complexes exhibited moderate toxicity. Interestingly, all complexes demonstrated negligible toxicity towards normal HEK-293 kidney cells (IC50 > 100 µM). The observed cytotoxicity of the complexes correlated well with their lipophilicities (dppz > dpq > phen). The cytotoxicity of complex 6 was comparable to that of the clinical drug cisplatin under similar conditions. Notably, neither the HQ nor the CQ ligands alone demonstrated noticeable toxicity against any of the tested cell lines. The Annexin-V-FITC and DCFDA assays revealed that the cell death mechanism induced by the complexes involved apoptosis, which could be attributed to the metal-assisted generation of reactive oxygen species. Overall, the dppz complex 6, with its remarkable cytotoxicity against a broad range of cancer cells and negligible toxicity toward normal cells, holds significant potential for cancer chemotherapeutic applications.

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.

AIM: This study evaluates the in vitro efficacy of 8-hydroxyquinoline (8HQ) derivatives in controlling the phytopathogenic fungus Phaeomoniella chlamydospora. METHODS AND RESULTS: 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, 1.01 µg mL-1, followed by captan (CAP), thiophanate methyl (TM), and mancozeb with MICs of 4.06, 5.46, and 10.62 µg mL-1, respectively. The 8HQ derivatives used in this study were clioquinol and PH 151 (PH) with MICs of 1.09 and 2.02 µg 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 + 0.0381 µg mL-1). CONCLUSIONS: 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. IMPACT STATEMENT: 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.

Cu(II) and Zn(II) Complexes of New 8-Hydroxyquinoline Schiff Bases: Investigating Their Structure, Solution Speciation, and Anticancer Potential.

We report the synthesis and characterization of three novel Schiff bases (L1-L3) derived from the condensation of 2-carbaldehyde-8-hydroxyquinoline with amines containing morpholine or piperidine moieties. These were reacted with CuCl2 and ZnCl2 yielding six new coordination compounds, with the general formula ML2, where M = Cu(II) or Zn(II) and L = L1-L3, which were all characterized by analytical, spectroscopic (Fourier transform infrared (FTIR), UV-visible absorption, nuclear magnetic resonance (NMR), or electron paramagnetic resonance (EPR)), and mass spectrometric techniques, as well as by single-crystal X-ray diffraction. In the solid state, two Cu(II) complexes, with L1 and L2, are obtained as dinuclear compounds, with relatively short Cu-Cu distances (3.146 and 3.171 Å for Cu2(L1)4 and Cu2(L2)4, respectively). The free ligands show moderate lipophilicity, while their complexes are more lipophilic. The pKa values of L1-L3 and formation constants of the complex (for ML and ML2) species were determined by spectrophotometric titrations, with the Cu(II) complexes showing higher stability than the Zn(II) complexes. EPR indicated the presence of several species in solution as pH varied and binding modes were proposed. The binding of the complexes to bovine serum albumin (BSA) was evaluated by fluorescence and circular dichroism (CD) spectroscopies. All complexes bind BSA, and as demonstrated by CD, the process takes several hours to reach equilibrium. The antiproliferative activity was evaluated in malignant melanoma cells (A375) and in noncancerous keratinocytes (HaCaT). All complexes display significant cytotoxicity (IC50 < 10 µM) but modest selectivity. The complexes show higher activity than the free ligands, the Cu(II) complexes being more active than the Zn(II) complexes, and approximately twice more cytotoxic than cisplatin. A Guava ViaCount assay corroborated the antiproliferative activity.

Low-dimensional compounds containing bioactive ligands. XXII. First crystal structure, cytotoxic activity and DNA and HSA binding of a zirconium(IV) complex with 8-hydroxyquinoline-2-carboxylic acid.

A new zirconium(IV) complex, diaquabis(8-hydroxyquinoline-2-carboxylato-κ3N,O2,O8)zirconium(IV) dimethylformamide disolvate, [Zr(C10H5NO3)2(H2O)2]·2C3H7NO or [Zr(QCa)2(H2O)2]·2DMF (1) (HQCaH is 8-hydroxyquinoline-2-carboxylic acid and DMF is dimethylformamide), was prepared and characterized by elemental analysis, IR spectroscopy and single-crystal X-ray structure analysis. Complex 1 is a mononuclear complex in which the ZrIV atoms sit on the twofold axis and they are octacoordinated by two N and six O atoms of two tridentate anionic QCa2- ligands, and two aqua ligands. Outside the coordination sphere are two DMF molecules bound to the complex unit by hydrogen bonds. The structure and stability of complex 1 in dimethyl sulfoxide were verified by NMR spectroscopy. The cytotoxic properties of 1 and HQCaH were studied in vitro against eight cancer cell lines, and their selectivity was tested on the BJ-5ta noncancerous cell line. Both the complex and HQCaH exhibited low activity, with IC50 > 200 µM. DNA and human serum albumin (HSA) binding studies showed that 1 binds to calf thymus (CT) DNA via intercalation and is able to bind to the tryptophan binding site of HSA (Trp-214).

Synthesis of Bioactive Aminomethylated 8-Hydroxyquinolines via the Modified Mannich Reaction.

8-hydroxyquinoline (oxine) is a widely known and frequently used chelating agent, and the pharmacological effects of the core molecule and its derivatives have been studied since the 19th century. There are several synthetic methods to modify this core. The Mannich reaction is one of the most easily implementable examples, which requires mild reaction conditions and simple chemical reagents. The three components of the Mannich reaction are a primary or secondary amine, an aldehyde and a compound having a hydrogen with pronounced activity. In the modified Mannich reaction, naphthol or a nitrogen-containing naphthol analogue (e.g., 8-hydroxyquinoline) is utilised as the active hydrogen provider compound, thus affording the formation of aminoalkylated products. The amine component can be ammonia and primary or secondary amines. The aldehyde component is highly variable, including aliphatic and aromatic aldehydes. Based on the pharmacological relevance of aminomethylated 8-hydroxyquinolines, this review summarises their syntheses via the modified Mannich reaction starting from 8-hydroxyquinoline, formaldehyde and various amines.

Synthesis and anticancer mechanisms of zinc(II)-8-hydroxyquinoline complexes with 1,10-phenanthroline ancillary ligands.

Twenty new zinc(II) complexes with 8-hydroxyquinoline (H-Q1-H-Q6) in the presence of 1,10-phenanthroline derivatives (D1-D10) were synthesized and formulated as [Zn(Q1)2(D1)] (DQ1), [Zn(Q2)2(D2)]·CH3OH (DQ2), [Zn(Q1)2(D3)] (DQ3), [Zn(Q1)2(D4)] (DQ4), [Zn(Q3)2(D5)] (DQ5), [Zn(Q3)2(D4)] (DQ6), [Zn(Q4)2(D5)]·CH3OH (DQ7), [Zn(Q4)2(D6)] (DQ8), [Zn(Q4)2(D3)]·CH3OH (DQ9), [Zn(Q4)2(D1)]·H2O (DQ10), [Zn(Q5)2(D4)] (DQ11), [Zn(Q6)2(D6)]·CH3OH (DQ12), [Zn(Q5)2(D2)]·5CH3OH·H2O (DQ13), [Zn(Q5)2(D7)]·CH3OH (DQ14), [Zn(Q5)2(D8)]·CH2Cl2 (DQ15), [Zn(Q5)2(D9)] (DQ16), [Zn(Q5)2(D1)] (DQ17), [Zn(Q5)2(D5)] (DQ18), [Zn(Q5)2(D10)]·CH2Cl2 (DQ19) and [Zn(Q5)2(D3)] (DQ20). They were characterized using multiple techniques. The cytotoxicity of DQ1-DQ20 was screened using human cisplatin-resistant SK-OV-3/DDP ovarian cancer (SK-OV-3CR) cells and normal hepatocyte (HL-7702) cells. Complex DQ6 showed low IC50 values (2.25 ± 0.13 µM) on SK-OV-3CR cells, more than 3.0-8.0 times more cytotoxic than DQ1-DQ5 and DQ7-DQ20 (≥6.78 µM), and even 22.2 times more cytotoxic than the standard cisplatin, the corresponding free H-Q1-H-Q6 and D1-D10 alone (>50 µM). As a comparison, DQ1-DQ20 displayed nontoxic rates against healthy HL-7702 cells. Furthermore, DQ6 and DQ11 induced significant apoptosis via mitophagy pathways. DQ6 also significantly inhibited tumor growth in an in vivo SK-OV-3-xenograft model (ca. 49.7%). Thus, DQ6 may serve as a lead complex for the discovery of new antitumor agents.

Design, synthesis, cytotoxic activities, and molecular docking of chalcone hybrids bearing 8-hydroxyquinoline moiety with dual tubulin/EGFR kinase inhibition.

The present study established thirteen novel 8-hydroxyquinoline/chalcone hybrids3a-mof hopeful anticancer activity. According to NCI screening and MTT assay results, compounds3d-3f, 3i,3k,and3ldisplayed potent growth inhibition on HCT116 and MCF7 cells compared to Staurosporine. Among these compounds,3eand3fshowed outstanding superior activity against HCT116 and MCF7 cells and better safety toward normal WI-38 cells than Staurosporine. The enzymatic assay revealed that3e,3d, and3ihad goodtubulin polymerization inhibition (IC50 = 5.3, 8.6, and 8.05 µM, respectively) compared to the reference Combretastatin A4 (IC50 = 2.15 µM). Moreover,3e,3l, and3fexhibited EGFR inhibition (IC50 = 0.097, 0.154, and 0.334 µM, respectively) compared to Erlotinib (IC50 = 0.056 µM). Compounds3eand3fwere investigated for their effects on the cell cycle, apoptosis induction, andwnt1/ß-cateningene suppression. The apoptosis markers Bax, Bcl2, Casp3, Casp9, PARP1, and ß-actin were detected by Western blot. In-silico molecular docking, physicochemical, and pharmacokinetic studies were implemented for the validation of dual mechanisms and other bioavailability standards. Hence, Compounds3eand3fare promising antiproliferative leads with tubulin polymerization and EGFR kinase inhibition.

Platinum(II) 5-substituted-8-hydroxyquinoline coordination compounds induces mitophagy-mediated apoptosis in A549/DDP cancer cells.

For the first time, two new mononuclear platinum(II) coordination compounds, [Pt(L1)(DMSO)Cl] (PtL1) and [Pt(L2)(DMSO)Cl] (PtL2) with the 5-(ethoxymethyl)-8-hydroxyquinoline hydrochloride (H-L1) and 5-bromo-8-hydroxyquinoline (H-L2) have been synthesized and characterized. The cytotoxic activity of PtL1 and PtL2 were screened in both healthy HL-7702 cell line and cancer cell lines, human lung adenocarcinoma A549 cancer cells and cisplatin-resistant lung adenocarcinoma A549/DDP cancer cells (A549R), and were compared to that of the H-L1, H-L2, H-L3 ligands and 8-hydroxyquinoline (H-L3) platinum(II) complex [Pt(L3)(DMSO)Cl] (PtL3). MTT results showed that PtL1 bearing one deprotonated L1 ligand against A549R was more potent by 8.8-48.6 fold than that of PtL2 and PtL3 complexes but was more selective toward healthy HL-7702 cells. In addition, PtL1 and PtL3 overcomes tumour drug resistance by significantly inducing mitophagy and causing the change of the related proteins expression, which leads to cell apoptosis. Moreover, the inhibitory effect of PtL1 on A549 xenograft tumour was 68.2%, which was much higher than that of cisplatin (cisPt, ca. 50.0%), without significantly changing nude mice weight in comparison with the untreated group. This study helps to explore the potential of the platinum(II) 5-substituted-8-hydroxyquinoline coordination compounds for the new Pt-resistant cancer therapy.

Evaluation of potential bacterial protease inhibitor properties of selected hydroxyquinoline derivatives: an in silico docking and molecular dynamics simulation approach.

Antimicrobial drug resistance (AMR) is a severe global threat to public health. The increasing emergence of drug-resistant bacteria requires the discovery of novel antibacterial agents. Quinoline derivatives have previously been reported to exhibit antimalarial, antiviral, antitumor, antiulcer, antioxidant and, most interestingly, antibacterial properties. In this study, we evaluated the binding affinity of three newly designed hydroxyquinolines derived from sulfanilamide (1), 4-amino benzoic acid (2) and sulfanilic acid (3) towards five bacterial protein targets (PDB ID: 1JIJ, 3VOB, 1ZI0, 6F86, 4CJN). The three derivatives were designed considering the amino acid residues identified at the active site of each protein involved in the binding of each co-crystallized ligand and drug-likeness properties. The ligands displayed binding energy values with the target proteins ranging from -2.17 to -8.45 kcal/mol. Compounds (1) and (3) showed the best binding scores towards 1ZI0/3VOB and 1JIJ/4CJN, respectively, which may serve as new antibiotic scaffolds. Our in silico results suggest that sulfanilamide (1) or sulfanilic acid (3) hydroxyquinoline derivatives have the potential to be developed as bacterial inhibitors, particularly MRSA inhibitors. But before that, it must go through the proper preclinical and clinical trials for further scientific validation. Further experimental studies are warranted to explore the antibacterial potential of these compounds through preclinical and clinical studies.Communicated by Ramaswamy H. Sarma.

Do bioactive 8-hydroxyquinolines oxidovanadium(IV) and (V) complexes inhibit the growth of M. smegmatis?

The antiproliferative effects of four series of VIVO- and VVO-based compounds containing 8-hydroxyquinoline ligands on the bacterium Mycolicibacterium smegmatis (M. smeg) were investigated. The effects on M. smeg were compared to the antiproliferative effects on the protozoan parasite Trypanosoma cruzi (T. cruzi), the causative agent for Chagas disease. In this study, we investigate the speciation of these compounds under physiological conditions as well as the antiproliferative effects on the bacterium M. smeg. We find that the complexes are more stable the less H2O is present, and that the stability increases in lipid-like environments. Only one heteroleptic complex and two homoleptic complexes were found to show similar antiproliferative effects on M. smeg as reported for T. cruzi so the responses generally observed by M.smeg. is less than observed by the pathogen. In summary, we find that M. smeg is more sensitive to the detailed structure of the V-complex but overall these complexes are less effective against M. smeg compared to T. cruzi.

Lysosome-targeted cyclometalated iridium(III) complexes: JMJD inhibition, dual induction of apoptosis, and autophagy.

A series of cyclometalated iridium(III) complexes with the formula [Ir(C^N)2 L](PF6) (C^N = 2-phenylpyridine (ppy, in Ir-1), 2-(2-thienyl)pyridine (thpy, in Ir-2), 2-(2,4-difluorophenyl)pyridine (dfppy, in Ir-3), L = 2-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)quinolin-8-ol) were designed and synthesized, which utilize 8-hydroxyquinoline derivative as N^N ligands to chelate the cofactor Fe2+ of the Jumonji domain-containing protein (JMJD) histone demethylase. As expected, the results of UV/Vis titration analysis confirm the chelating capabilities of Ir-1-3 for Fe2+, and molecular docking studies also show that Ir-1-3 can interact with the active pocket of JMJD protein, and treatment of cells with Ir-1-3 results in significant upregulation of trimethylated histone 3 lysine 9 (H3K9Me3), indicating the inhibition of JMJD activity. Meanwhile, Ir-1-3 exhibit much higher cytotoxicity against the tested tumor cell lines compared with the clinical chemotherapeutic agent cisplatin. And Ir-1-3 can block the cell cycle at the G2/M phase and inhibit cell migration and colony formation. Further studies show that Ir-1-3 can specifically accumulate in lysosomes, damage the integrity of lysosomes, and induce apoptosis and autophagy. Reduction of mitochondrial membrane potential and elevation of reactive oxygen species also contribute to the antitumor effects of Ir-1-3. Finally, Ir-1 can inhibit tumor growth effectively in vivo and increase the expression of H3K9Me3 in tumor tissues. Our study demonstrates that these iridium(III) complexes are promising anticancer agents with multiple functions, including the inhibition of JMJD and induction of apoptosis and autophagy.

Alzheimer's Drug PBT2 Interacts with the Amyloid ß 1-42 Peptide Differently than Other 8-Hydroxyquinoline Chelating Drugs.

Although Alzheimer's disease (AD) was first described over a century ago, it remains the leading cause of age-related dementia. Innumerable changes have been linked to the pathology of AD; however, there remains much discord regarding which might be the initial cause of the disease. The "amyloid cascade hypothesis" proposes that the amyloid ß (Aß) peptide is central to disease pathology, which is supported by elevated Aß levels in the brain before the development of symptoms and correlations of amyloid burden with cognitive impairment. The "metals hypothesis" proposes a role for metal ions such as iron, copper, and zinc in the pathology of AD, which is supported by the accumulation of these metals within amyloid plaques in the brain. Metals have been shown to induce aggregation of Aß, and metal ion chelators have been shown to reverse this reaction in vitro. 8-Hydroxyquinoline-based chelators showed early promise as anti-Alzheimer's drugs. Both 5-chloro-7-iodo-8-hydroxyquinoline (CQ) and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline (PBT2) underwent unsuccessful clinical trials for the treatment of AD. To gain insight into the mechanism of action of 8HQs, we have investigated the potential interaction of CQ, PBT2, and 5,7-dibromo-8-hydroxyquinoline (B2Q) with Cu(II)-bound Aß(1-42) using X-ray absorption spectroscopy (XAS), high energy resolution fluorescence detected (HERFD) XAS, and electron paramagnetic resonance (EPR). By XAS, we found CQ and B2Q sequestered ∼83% of the Cu(II) from Aß(1-42), whereas PBT2 sequestered only ∼59% of the Cu(II) from Aß(1-42), suggesting that CQ and B2Q have a higher relative Cu(II) affinity than PBT2. From our EPR, it became clear that PBT2 sequestered Cu(II) from a heterogeneous mixture of Cu(II)Aß(1-42) species in solution, leaving a single Cu(II)Aß(1-42) species. It follows that the Cu(II) site in this Cu(II)Aß(1-42) species is inaccessible to PBT2 and may be less solvent-exposed than in other Cu(II)Aß(1-42) species. We found no evidence to suggest that these 8HQs form ternary complexes with Cu(II)Aß(1-42).

New ternary Fe(III)-8-hydroxyquinoline-reduced Schiff base complexes as selective anticancer drug candidates.

Due to the growing prevalence of cancer diseases, new therapeutic options are urgently needed, and drugs based on metal ions other than platinum are alternatives with exciting possibilities. We report the synthesis, characterization and biological effect of mixed-ligand Fe(III)-aminophenolate complexes derived from salicylaldehyde and L-tryptophan with quinoline derivatives as co-ligands, namely 8-hydroxyquinoline (8HQ), [Fe(L)(8HQ)(H2O)] (1) and its 5-cloro derivative (Cl8HQ), [Fe(L)(Cl8HQ)(H2O)] (2). The complex bearing the aminophenolate and lacking the quinoline co-ligand, [Fe(L)(Cl)(H2O)2] (3), was prepared for comparison. The analytical and spectroscopic characterization revealed that 1 and 2 are octahedral Fe(III) complexes with the aminophenolate acting as a dianionic tridentate ligand and 8HQ co-ligands as bidentate chelates. Spectroscopic techniques and molecular docking studies were used to evaluate the ability of these complexes to bind bovine serum albumin (BSA) and calf thymus DNA. Complex 2 [Fe(L)(Cl8HQ)(H2O)] was the one showing higher affinity for both biomolecules. Cell viability was assessed in breast, colorectal and bone human cancer cell lines. 1 and 2 were found to be more active than cisplatin in all cell lines tested. A non-tumoral fibroblast line (L929, mouse non-tumoral fibroblasts) was used to evaluate selectivity. The results evidence that 2 shows much higher selectivity than 1 in all cell lines tested, but particularly in bone cancer cells in which selectivity index (SI) values are 8.0 and 18.8 for 1 and 2, respectively.

Discovery of quinolinequinones with N-phenylpiperazine by conversion of hydroxyquinoline as a new class of antimicrobial agents targeting resistant pathogenic microorganisms.

The development of new antimicrobial agents is necessary to overcome the emerging antimicrobial resistance among infectious microbial pathogens. Herein, we successfully designed and synthesized quinolinequinones (QQs) with N-phenylpiperazine (QQ1-7) containing strong or weak EDG in the amino moiety by converting hydroxyquinoline (HQ) to the dichloroquinolinequinone (QQ) via chlorooxidation. We performed an extensive antimicrobial activity assessment of the QQs with N-phenylpiperazine (QQ1-7). Among the seven quinolinequinones (QQs) with N-phenylpiperazine tested, QQ3 and QQ4 were the most active molecules against Staphylococcus aureus (ATCC® 29213) with a MIC value of 1.22 µg/mL. In addition to this, while QQ4 was more than six (6) times more effective towards Enterococcus faecalis (ATCC® 29212), QQ3 was twenty-six (26) times more effective against same strain. Furthermore, the evaluation of antimicrobial activity indicated that six of seven synthesized QQs (QQ1-4, QQ6, and QQ7) exhibited superior biological potency, eight (8) times for five of them (QQ1-4 and QQ6) and two (2) times for QQ7, against Staphylococcus epidermidis (ATCC® 12228). Besides, all QQs except QQ5 displayed excellent antifungal activity against the fungi Candida albicans (ATCC® 10231). Among these, the two QQs (QQ3 and QQ4), which showed the lowest values against gram-positive bacterial strains (Staphylococcus aureus (ATCC® 29213), Staphylococcus epidermidis (ATCC® 12228), and Enterococcus faecalis (ATCC® 29212)) as well as fungal strains (Candida albicans (ATCC® 10231) and Candida parapsilosis (ATCC® 22019)), were further evaluated for their biofilm inhibition properties and their mode of action with in vitro potential antimicrobial activity against each of 20 clinically obtained resistant strains of gram-positive bacteria, and bactericidal activity using time-kill curve assay. In this study, we investigated the bactericidal effects of QQ3 against methicillin-resistant Staphylococcus aureus (MRSA) and Candida albicans strains. The findings of this study suggest that a significant bactericidal effect was seen with all tested 1 × MIC and 4 × MIC concentrations used within 24 h. Our findings present significant implications for an antimicrobial drug candidate for treating infections, especially those caused by clinically resistant MRSA isolates.

Solution chemical properties and anticancer potential of 8-hydroxyquinoline hydrazones and their oxidovanadium(IV) complexes.

We report the synthesis and characterization of a family of benzohydrazones (Ln, n = 1-6) derived from 2-carbaldehyde-8-hydroxyquinoline and benzylhydrazides containing different substituents in the para position. Their oxidovanadium(IV) complexes were prepared and compounds with 1:1 and 1:2 metal-to-ligand stoichiometry were obtained. All compounds were characterized by elemental analyses and mass spectrometry as well as FTIR, UV-visible absorption, NMR (ligand precursors) and EPR (complexes) spectroscopies, and by DFT computational methods. Proton dissociation constants, lipophilicity and solubility in aqueous media were determined for all ligand precursors. Complex formation with V(IV)O was evaluated by spectrophotometry for L4 (Me-substituted) and L6 (OH-substituted) and formation constants for mono [VO(HL)]+, [VO(L)] and bis [VO(HL)2], [VO(HL)(L)]-, [VO(L)2]2- complexes were determined. EPR spectroscopy indicates the formation of [VO(HL)]+ and [VO(HL)2], with this latter being the major species at the physiological pH. Noteworthy, the EPR data suggest a different behaviour for L4 and L6, which confirm the results obtained in the solid state. The antiproliferative activity of all compounds was evaluated in malignant melanoma (A-375) and lung (A-549) cancer cells. All complexes show much higher activity on A-375 (IC50 < 6.3 µM) than in A-549 cells (IC50 > 20 µM). Complex 3 (F-substituted) shows the lowest IC50 on both cell lines and lower than cisplatin (in A-375). Studies identified this compound as the one showing the highest increase in Annexin-V staining, caspase activity and induction of double stranded breaks, corroborating the cytotoxicity results. The mechanism of action of the complexes involves reactive oxygen species (ROS) induced DNA damage, and cell death by apoptosis.

8-Hydroxyquinoline-modified ruthenium(II) polypyridyl complexes for JMJD inhibition and photodynamic antitumor therapy.

As an ideal scaffold for metal ion chelation, 8-hydroxyquinoline (8HQ) can chelate different metal ions, such as Fe2+, Cu2+, Zn2+, etc. Here, by integrating 8HQ with a ruthenium(II) polypyridyl moiety, two Ru(II)-8HQ complexes (Ru1 and Ru2), [Ru(N-N)2L](PF6)2 (L = 2-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)quinolin-8-ol; N-N: 2,2'-bipyridine (bpy, in Ru1), 1,10-phenanthroline (phen, in Ru2)) were designed and synthesized. In both complexes, ligand L is an 8HQ derivative designed to chelate the cofactor Fe2+ of jumonji C domain-containing demethylase (JMJD). As expected, Ru1 and Ru2 could inhibit the activity of JMJD by chelating the key cofactor Fe2+ of JMJD, resulting in the upregulation of histone-methylation levels in human lung cancer (A549) cells, and the upregulation was more pronounced under light conditions. In addition, MTT data showed that Ru1 and Ru2 exhibited lower dark toxicity, and light irradiation could significantly enhance their antitumor activity. The marked photodynamic activities of Ru1 and Ru2 could induce the elevation of reactive oxygen species (ROS), depolarization of mitochondrial membrane potential (MMP), and activation of caspases. These mechanistic studies indicated that Ru1 and Ru2 could induce apoptosis through the combination of JMJD inhibitory and PDT activities, thereby achieving dual antitumor effects.

Iron chelation and inhibition of metallopeptidases mediate anti-Trichomonas vaginalis activity by a novel 8-hydroxyquinoline derivative.

Trichomoniasis is a neglected parasitic infection, with no oral therapeutic alternatives to overcome the pitfalls of currently approved drugs. In this context, the search for new anti-Trichomonas vaginalis drugs is imperative. Here we report the selective anti-T. vaginalis activity of a substituted 8-hydroxyquinoline-5-sulfonamide derivative. Six different derivatives were evaluated for anti-T. vaginalis. In vitro and in vivo toxicity methods, association with metal ions, and investigation on the mechanism of action were performed with the most active derivative, PH 152. Cytotoxicity assays showed selectivity for the parasite and the low toxicity was confirmed in G. mellonella larvae model. The mode of action is related to iron chelation by disrupting Fe-S clusters-dependent enzyme activities in the parasite. Proteomic analysis indicated inhibition of metallopeptidases related to T. vaginalis virulence mechanisms and metabolic pathways. PH 152 presented selective trichomonacidal activity through multitarget action.

Identification of 8-Hydroxyquinoline Derivatives That Decrease Cystathionine Beta Synthase (CBS) Activity.

CBS encodes a pyridoxal 5'-phosphate-dependent enzyme that catalyses the condensation of homocysteine and serine to form cystathionine. Due to its implication in some cancers and in the cognitive pathophysiology of Down syndrome, the identification of pharmacological inhibitors of this enzyme is urgently required. However, thus far, attempts to identify such molecules have only led to the identification of compounds with low potency and limited selectivity. We consequently developed an original, yeast-based screening method that identified three FDA-approved drugs of the 8-hydroxyquinoline family: clioquinol, chloroxine and nitroxoline. These molecules reduce CBS enzymatic activity in different cellular models, proving that the molecular mechanisms involved in yeast phenotypic rescue are conserved in mammalian cells. A combination of genetic and chemical biology approaches also revealed the importance of copper and zinc intracellular levels in the regulation of CBS enzymatic activity-copper promoting CBS activity and zinc inhibiting its activity. Taken together, these results indicate that our effective screening approach identified three new potent CBS inhibitors and provides new findings for the regulation of CBS activity, which is crucial to develop new therapies for CBS-related human disorders.