We synthesized a new series of conjugated hydrazones that were found to be active against malaria parasite in vitro, as well as in vivo in a murine model. These hydrazones concentration-dependently ...chelated free iron and offered antimalarial activity. Upon screening of the synthesized hydrazones, compound 5f was found to be the most active iron chelator, as well as antiplasmodial. Compound 5f also interacted with free heme (KD equilibrium dissociation constant = 1.17 ± 0.8 μM), an iron-containing tetrapyrrole released after hemoglobin digestion by the parasite, and inhibited heme polymerization by parasite lysate. Structure-activity relationship studies indicated that a nitrogen- and sulfur-substituted five-membered aromatic ring present within the benzothiazole hydrazones might be responsible for their antimalarial activity. The dose-dependent antimalarial and heme polymerization inhibitory activities of the lead compound 5f were further validated by following (3)Hhypoxanthine incorporation and hemozoin formation in parasite, respectively. It is worth mentioning that compound 5f exhibited antiplasmodial activity in vitro against a chloroquine/pyrimethamine-resistant strain of Plasmodium falciparum (K1). We also evaluated in vivo antimalarial activity of compound 5f in a murine model where a lethal multiple-drug-resistant strain of Plasmodium yoelii was used to infect Swiss albino mice. Compound 5f significantly suppressed the growth of parasite, and the infected mice experienced longer life spans upon treatment with this compound. During in vitro and in vivo toxicity assays, compound 5f showed minimal alteration in biochemical and hematological parameters compared to control. In conclusion, we identified a new class of hydrazone with therapeutic potential against malaria.
Efficient synthetic procedures for the preparation of acid hydrazines and hydrazides were developed by converting the corresponding carboxylic acid into the methyl ester catalyzed by Amberlyst-15, ...followed by a reaction with hydrazine monohydrate. Sulfohydrazides were prepared from the corresponding sulfonyl chlorides and hydrazine monohydrate. Both of these group of compounds were condensed with substituted salicylaldehydes using gradient concentration methods that generated a large library of hydrazone, hydrazide and sulfohydrazide analogs. Antifungal activity of the prepared analogs showed that salicylaldehyde hydrazones and hydrazides are potent inhibitors of fungal growth with little to no mammalian cell toxicity, making these analogs promising new targets for future therapeutic development.
Donor and donor-donor carbenes are two important kinds of carbenes, which have experienced tremendous growth in the past two decades. This review provides a comprehensive overview of the recent ...development of donor and donor-donor carbene chemistry. The development of this chemistry offers efficient protocols to construct a wide variety of C-C and C-X bonds in organic synthesis. This review is organized based on the different types of carbene precursors, including diazo compounds, hydrazones, enynones, cycloheptatrienes and cyclopropenes. The typical transformations, the reaction mechanisms, as well as their subsequent applications in the synthesis of complex natural products and bioactive molecules are discussed. Due to the rapidly increasing interest in this area, we believe that this review will provide a timely and comprehensive discussion of recent progress in donor and donor-donor carbene chemistry.
The Cover Feature highlights the Latin American culture with an emblem that is the accordion and how the versatility of the amino group resembles the musical notes that appropriately combined exhibit ...multiple dynamics in the hydrazones. Each highlighted hydrazone‐based system represents one type of dynamism: conformational (orange), configurational (blue), and constitutional (green). The harmonic box contains the words “amino group” to remark the particularly important role of the N–H group in each of those processes observed in hydrazone‐based molecular and supramolecular systems. The authors thank Alejandro Ijaji for the extraordinary design of the cover, following the concept given by the authors. More information can be found in the Review by M. N. Chaur et al.
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•The synthesis of a series of novel macrocyclic hydrazone compounds bearing isovanilline moiety (GY1-12) was reported.•ALR2 enzyme was purified with 2.99% yield and 2.10 EU/mg ...specific activity.•All compounds exhibited a high inhibitory effect on ALR2 as competitive and non-competitive inhibition types.•In silico, molecular docking was carried out to study binding of the most active compounds.
Aldose reductase (ALR2), one of the metabolically important enzymes, catalyzes the formation of sorbitol from glucose in the polyol pathway. ALR2 inhibition is required to prevent diabetic complications. In the present study, the novel bis-hydrazone compounds bearing isovanillin moiety (GY1-12) were synthesized, and various chromatographic methods were applied to purify the ALR2 enzyme. Afterward, the inhibitory effect of the synthesized compounds on the ALR2 was screened in vitro. All the novel bis-hydrazones demonstrated activity in nanomolar levels as AR inhibitors with IC50 and KI values in the range of 12.55–35.04 nM, and 13.38–88.21 nM, respectively. Compounds GY-11, GY-7, and GY-5 against ALR2 were identified as the highly potent inhibitors, respectively, and were superior to the standard drug, epalrestat. Moreover, a comprehensive ligand-receptor interactions prediction was performed using ADME-Tox, Glide XP, and MM-GBSA modules of Schrödinger Small-Molecule Drug Discovery Suite to elucidate the novel bis-hydrazone derivatives, potential binding modes versus the ALR2. As a result, these compounds with ALR2 inhibitory effects may be potential alternative agents that can be used to treat or prevent diabetic complications.
Levosimendan for Hemodynamic Support after Cardiac Surgery Landoni, Giovanni; Lomivorotov, Vladimir V; Alvaro, Gabriele ...
New England journal of medicine/The New England journal of medicine,
05/2017, Volume:
376, Issue:
21
Journal Article
Peer reviewed
Open access
Acute left ventricular dysfunction is a major complication of cardiac surgery and is associated with increased mortality. Meta-analyses of small trials suggest that levosimendan may result in a ...higher rate of survival among patients undergoing cardiac surgery.
We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving patients in whom perioperative hemodynamic support was indicated after cardiac surgery, according to prespecified criteria. Patients were randomly assigned to receive levosimendan (in a continuous infusion at a dose of 0.025 to 0.2 μg per kilogram of body weight per minute) or placebo, for up to 48 hours or until discharge from the intensive care unit (ICU), in addition to standard care. The primary outcome was 30-day mortality.
The trial was stopped for futility after 506 patients were enrolled. A total of 248 patients were assigned to receive levosimendan and 258 to receive placebo. There was no significant difference in 30-day mortality between the levosimendan group and the placebo group (32 patients 12.9% and 33 patients 12.8%, respectively; absolute risk difference, 0.1 percentage points; 95% confidence interval CI, -5.7 to 5.9; P=0.97). There were no significant differences between the levosimendan group and the placebo group in the durations of mechanical ventilation (median, 19 hours and 21 hours, respectively; median difference, -2 hours; 95% CI, -5 to 1; P=0.48), ICU stay (median, 72 hours and 84 hours, respectively; median difference, -12 hours; 95% CI, -21 to 2; P=0.09), and hospital stay (median, 14 days and 14 days, respectively; median difference, 0 days; 95% CI, -1 to 2; P=0.39). There was no significant difference between the levosimendan group and the placebo group in rates of hypotension or cardiac arrhythmias.
In patients who required perioperative hemodynamic support after cardiac surgery, low-dose levosimendan in addition to standard care did not result in lower 30-day mortality than placebo. (Funded by the Italian Ministry of Health; CHEETAH ClinicalTrials.gov number, NCT00994825 .).
Drug resistance is a major impediment for cancer treatment, to overcome it we designed and synthesized sixteen coumarins bearing hydrazide–hydrazone moiety and evaluated them against human ...drug-resistant pancreatic carcinoma (Panc-1) cells and drug-sensitive (hepatic carcinoma; Hep-G2 and leukemia; CCRF) cell lines in vitro. The 6-brominated coumarin hydrazide–hydrazone derivatives (BCHHD) 7c, 8c and 10c were more potent than doxorubicin (DOX) against resistant Panc-1 cells. BCHHD 7c showed significant cytotoxicity against all tested cells (IC50: 3.60–6.50 μM) on comparison with all other coumarin hydrazide–hydrazone derivatives (CHHD), whereas BCHHD's 8c and 10c showed significant antiproliferative activity only against resistant Panc-1 cells with IC50 of 2.02 μM and 2.15 μM, respectively. All the investigated BCHHD's were able to activate caspases 3/7 and they could induce apoptosis in resistant Panc-1 cells. Microarray analysis showed that BCHHD 7c induced the expression of apoptotic- and cell cycle arrest (G2/M)- genes in resistant Panc-1 cells. Moreover, BCHHD 7c induced the up-regulation of CDKN1A, DDIT4, GDF-15 and down-regulation of CDC2, CDC20, CDK2 genes. Based on our results, we conclude that 7c could be a potent anticancer drug to overcome drug resistance in cancer and it could be highly beneficial for patients in the clinic.
New series of coumarins were synthesized and evaluated in vitro for their anticancer activity. Bromocoumarins were found to be the most active antitumor agent against drug-resistant pancreatic carcinoma cells. Display omitted
•Sixteen coumarin hydrazide–hydrazone derivatives were synthesized.•Bromocoumarins showed potent antitumor activity against Panc-1 cancer cell line.•Bromocoumarins activated caspases 3/7 and they could induce apoptosis.•Coumarin 7c induced the expression of cell cycle arrest (G2/M) genes.•Coumarin 7c induced up- and down-regulation of several genes.
A novel series of 1-acylthiosemicarbazides, 1,2,4-triazole-5-thiones, 1,3,4-thiadiazoles and hydrazones containing 5-methyl-2-benzoxazolinones was synthesized and investigated for their ...antiinflammatory and analgesic activity as well as antimicrobial activity.
Acetic acid hydrazide containing 5-methyl-2-benzoxazolinone (
4) was synthesized by the condensation of 2-(5-methyl-2-benzoxazolinone-3-yl)acetate with hydrazine hydrate. Thiosemicarbazide derivatives (
5a–
5d) were afforded by the reaction of corresponding compound
4 with substituted isothiocyanates. The cyclization of compounds
5a–
5d in the presence of triethylamine resulted in the formation of compounds
6a–
6d containing 1,2,4-triazole ring. On the other hand, the treatment of compounds
5a–
5d with orthophosphoric acid caused the conversion of side chain of compounds
5a–
5d into 1,3,4-thiadiazole ring: thus, compounds
7a–
7c were obtained. The treatment of compound
4 with aromatic aldehydes resulted in the formation of arylidene hydrazides as
cis–
trans conformers (
8a–
8e). The structures of the compounds were elucidated by spectral and elemental analysis. While most compounds were exhibiting high activity in the analgesic-anti-inflammatory field, most of them were found to be inactive against bacteria and fungi.
A macrocyclic hydrazone Schiff base was synthesized by reacting 1,4-dicarbonyl phenyl dihydrazide with 2,6-diformyl-4-methyl phenol and a series of metal complexes with this new Schiff base were ...synthesized by reaction with Co(II), Ni(II) and Cu(II) metal salts. The Schiff base and its complexes have been characterized by elemental analyses, IR,
1H NMR, UV–vis, FAB mass, ESR spectra, fluorescence, thermal, magnetic and molar conductance data. The analytical data reveal that the Co(II), Ni(II) and Cu(II) complexes possess 2:1 metal–ligand ratios. All the complexes are non-electrolytes in DMF and DMSO due to their low molar conductance values. Infrared spectral data suggest that the hydrazone Schiff base behaves as a hexadentate ligand with NON NON donor sequence towards the metal ions. The ESR spectral data shows that the metal–ligand bond has considerable covalent character. The electrochemical behavior of the copper(II) complex was investigated by cyclic voltammetry. The Schiff base and its complexes have also been screened for their antibacterial (
Escherichia coli,
Staphylococcus aureus,
Shigella dysentery,
Micrococcus,
Bacillus subtilis,
Bacillus cereus and
Pseudomonas aeruginosa) and antifungal activities (
Aspergillus niger,
Penicillium and
Candida albicans) by MIC method. The brine shrimp bioassay was also carried out to study their
in-vitro cytotoxic properties.
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•Indole hydrazones were designed and easy synthesized.•Synthesized compounds were assayed in vitro as antioxidants and photoprotective agents.•Synthesized compounds were assayed in ...vitro for their antiproliferative activity on human melanoma and leukemia cells.•The hydrazones 16 and 17 showed antioxidant activity in DPPH, FRAP and ORAC test as well as photoprotective effect.•The hydrazones 11, 16 and 17 inhibited the growth of Colo-38 and K-562 cells with sub-micromolar IC50 values.
Two series of indole derivatives 4–17, 20–22 were easily prepared and assayed for their radical-scavenging ability. Arylidene-1H-indole-2-carbohydrazones showed different extent antioxidant activity in DPPH, FRAP and ORAC assays. Good antioxidant activity is related to the number and position of hydroxyl groups on the arylidene moiety as well as to the presence of methoxy or 4-(diethylamino) group. On the contrary low antioxidant activity is showed by the isomeric 1H-indol-2-yl(methylene)-benzohydrazides. Furthermore, hydrazones 4–17 showed photoprotective capacities with satisfactory in vitro SPF as compared to the commercial PBSA sunscreen filter. The indole 16 and 17, showing the best antioxidant and photoprotective profile, were included in different formulation and their topical release was evaluated. Varying the formulation composition, it was possible to optimize skin adsorption and solubility of the active indole in the formulation. The antiproliferative effect of the hydrazones 4–17 was tested on human erythroleukemia K562 and melanoma Colo-38 cells. Hydrazones 11, 16 and 17 showed growth inhibition at sub micromolar concentrations on both cell lines. These results indicate indole hydrazones as potential multifunctional molecules especially in the treatment of neoplastic diseases being the good antioxidant properties of 16 and 17 correlated to their high antiproliferative activity.
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