Synthesis, characterization, and antibacterial activity of a novel heterocyclic Schiff’s base and its metal complexes of first transition series

The synthesis of a series of some novel Schiff base complexes of Cu(II), Ni(II), Co(II), Mn(II), Zn(II) with a tetradentate Schiff base has been achieved by the reaction of malonyl hydrazide with dehydroacetic acid in ethanol under refluxing condition. All the synthesized metal complexes and ligand were characterized on the basis of elemental analysis, UV–Visible, ¹H and ¹³C NMR, IR spectroscopy and mass spectrometry. The IR spectral data suggest that azomethine N and enolic O atom are involved in coordination with metal ions, and the ligand behaves as a tetradentate ligand with ONNO donor atoms. The mass spectrum of the complexes reveals the formation of metal ligand bonding in stoichiometric ratio 1:1 (M:L). The UV–Visible data suggest the square planner geometry for the synthesized complexes. All compounds were screened for their antibacterial activity against gram-positive and gram-negative bacteria using Ampicillin as a standard drug. It has been found that metal complexes show enhanced activity as compared to ligand, and some modification in ligand structure may lead to better antibacterial agents in future.     

Synthesis,characterization, DNA interaction,and antitumor activities of mixed-ligand metal complexes of kaempferol and 1,10-phenanthroline/2,2′-bipyridine

Four novel mixed-ligand metal complexes with the composition [Cu(Kae)(phen)]Cl·2H₂O (1), [Cu(Kae)(bpy)]Cl·H₂O (2), [Zn(Kae)(phen)]Cl·H₂O (3), and [Zn(Kae)(bpy)]Cl·H₂O (4), where Kae = kaempferol, phen = 1,10-phenanthroline, bpy = 2,2′-bipyridine were synthesized and characterized by elemental analysis, IR, UV, ¹H NMR, ¹³C NMR, HRMS ,and molar conductivity. The binding and cleavage abilities of complexes 1–4 with DNA have been studied by fluorescence spectroscopy, viscosity measurements, and gel electrophoresis under physiological conditions. The experimental results indicated that four complexes could bind to CT-DNA via an intercalative mode, and the complex 1 showed the strongest activity to cleavage DNA (pUC 19). The in vitro cytotoxicities of kaempferol and complexes 1–4 were also evaluated against human breast carcinoma cells by MTT assays. The results show that the cytotoxicities of complexes 1–4 are much higher than that of kaempferol alone, and the complex 1 shows the strongest ability to inhibit the growth of human breast carcinoma cells. The results suggest that the complex 1 may be a valuable tool in cancer chemotherapy agents.     

Synthesis,structural elucidation and bioevaluation of 4-amino-1,2,4-triazole-3-thione’s Schiff base derivatives

In this study, a series of ten triazole Schiff base derivatives 6a–j were synthesized through microwave assisted imine formation by reacting substituted amino triazole 5 with different substituted aldehydes. All the synthesized compounds were evaluated for their inhibitory activity against mushroom tyrosinase. Two of the compounds 6a and 6b among the series 6a–j were found to be highly potent tyrosinase inhibitors with IC₅₀ values of 10.09 ± 1.03 and 6.23 ± 0.85 µM, respectively, which were even higher than that of the reference inhibitor kojic acid (IC₅₀ = 16.6 ± 2.8 µM). Compounds 6e and 6f with IC₅₀ values of 20.27 ± 2.78 and 26.02 ± 4.14 µM, respectively, were comparable to the reference inhibitor, and the remaining compounds had a moderate inhibitory activity against mushroom tyrosinase. The most potent compounds (6a, 6b) were used in the kinetic and optical analyses. The inhibition kinetics analyzed with Lineweaver–Burk plots revealed that both compounds 6a and 6b were non-competitive inhibitors of tyrosinase with inhibition constant values of 0.023 and 0.022 mM, respectively.     

Synthesis, antimicrobial and cytotoxic activities of novel 4-trifluoromethyl-(1,2,3)-thiadiazolo-5-carboxylic acid hydrazide Schiff’s bases

A series of novel 1,2,3-thiadiazolo-5-carboxylic acid hydrazide Schiff’s bases 4a–4r were prepared starting from ethyl-4,4,4-trifluoroacetoacetate and ethyl carbazate in four steps. All the compounds were screened for antibacterial activity against various bacterial strains at 150 μg/ml concentration and found no activity. Similarly, all the compounds were screened for antifungal activity against various fungal strains at 100 and 150 μg/ml concentrations. Compounds 4a, 4m, and 4q found to show moderate activity against Candida albicans. Further, compounds were evaluated for cytotoxic activity against breast carcinoma cells MDA-MB 231 (aggressive), MCF-7 (non-aggressive) using doxorubicin as standard. Compound 4n was found to show 25.39 % cell viability against MDA-MB 231 and 63.60 % cell viability against MCF-7 cells.     

Synthesis of metal(II) [M = Cu, Mn, Zn] Schiff base complexes and their Pro-apoptotic activity in liver tumor cells via caspase activation

Hepatocellular carcinoma is the fifth most common cancer responsible for more than 600,000 deaths per year. It is a typical vascular tumor which at earlier stages does not exhibit remarkable development of tumor; however, at advance stages, it is richly supplied by blood vessels and damages hepatocyte, the main functional cell types in the liver. Currently, surgery and chemotherapy are the main treatment strategies. However, the chemotherapeutic agents are usually unable to discriminate between normal and cancerous cells, and hence adverse effects of drug toxicities have become the major concerns in chemotherapy. Thus, inducing caspase dependent cytotoxicity in cancer cells via apoptosis has become one of the interesting and effective strategies for fighting this disease. The current study is an effort to further explore this area of research. Mn(II), Cu(II), and Zn(II) Schiff base complexes were prepared by condensation of 2-hydroxy-1-naphthaldehyde with either 4-nitrobenzene-1,2-diamine or 4-methylbenzene-1,2-diamine and characterized by Spectroscopic (FT-IR, UV–Vis, NMR, and MS) and microanalysis. The ligands, in comparison to their metal complexes, were evaluated for their anticancer and proapoptotic properties in human hepatocarcinoma (HepG2) cells. Results showed that the complexes are more potent proapoptotic agents than the parent ligands. All the tested compounds showed dose-dependent antiproliferative activity comparable with 5-fluorouracil (IC₅₀ = 4.6 μg/mL). All the synthesized Schiff base ligands and respective metal complexes showed potential anticancer activity. Out of them, some compounds showed IC₅₀ value as low as 1.24–3.56 μg/mL. Compounds 3 and 7 inhibited HepG2 cell proliferation by inducing apoptosis via activation of caspase cascade.     

Synthesis, characterization, and in vitro antiproliferative activity of novel β-elemene monosubstituted derivatives

A series of β-elemene monosubstituted ester, carbamate, acylamide, and carbamidine derivatives were synthesized via intermediates, β-elemene alcohol and β-elemene amine, which were synthesized from the traditional Chinese medicine, β-elemene. The structures of all the new compounds were characterized by NMR, IR, and HRMS. Their in vitro antiproliferative activities on HeLa cell line were tested through the WST-1 assay. The results show that the in vitro antiproliferative activities of the novel compounds are improved compared to that of the parent β-elemene.     

Docking-based virtual screening of Schiff’s bases of GABA: a prospective to novel GABA-AT inhibitors

The accurate prediction of the binding modes between the ligand and protein is of fundamental importance in modern structure-based drug design. In this study, computational ligand docking methodology, AutoDock 4.0, based on Lamarckian genetic algorithm was employed for virtual screens of a compound library with 233 entries (Schiff’s bases of γ-amino butyric acid) for novel and selective inhibitors of the enzyme γ-amino butyrate aminotransferase (GABA-AT), a potential anticonvulsant drug target. Considering free energy of binding and inhibition constant (KI) as a criteria of evaluation, a total of 43 compounds were predicted to be potential inhibitors of GABA-AT and 11 compounds displayed greater binding affinities than γ-vinyl GABA, Vigabatrin, a well-known GABA-AT inhibitor. Compound SBG164, a dibenzylideneacetone analog; compound SBG195, a 1-methylanthraquinone analog; and compound SBG110, a fenchone analog were the most potent in inhibiting the GABA-AT, in silico. Putative interactions between GABA-AT and inhibitors were identified by inspection of docking-predicted poses. This understanding of protein–ligand interaction and value of KI imparts impetus to the rapid development of prospective GABA-AT inhibitor. It also helps to eliminate the number of false positives and negatives.     

Pimavanserin,a novel antipsychotic for management of Parkinson’s disease psychosis

Introduction: Parkinson’s disease psychosis (PDP) may develop in up to 60% of Parkinson’s patients and is associated with increased morbidity and mortality. It also correlates with depression and dementia, and can contribute to caregiver stress and burnout. Pimavanserin is the first FDA approved drug for the treatment of hallucinations and delusions associated with PDP.

Areas covered: For this review, a MEDLINE literature search (via PubMed) and information provided by ACADIA Pharmaceuticals were used. This review will discuss the pathophysiology and current management of PDP. In addition, this review will focus on the rationales behind the development of pimavanserin, mechanism of action, pharmacokinetics, pharmacodynamics, and the clinical trials evaluating the efficacy and safety of pimavanserin. Last, the review will address the drug’s package insert warning.

Expert commentary: Pimavanserin, a 5HT2A receptor inverse agonist, is the first FDA approved drug for the treatment of PDP which has been shown to reduce psychosis in PD through its unique mechanism of action. Pimavanserin, does not worsen PD motor symptoms and has an acceptable safety profile. The development of pimavanserin as an antipsychotic opened a new therapeutic avenue in the treatment of PDP as well as targeting psychosis in other disorders such as Alzheimer’s disease.     

Synthesis, characterization, and antitumor activities of 1,1′-diacetylferrocene dihydrazone containing phenolic group and its complexes with Pd(II) and Pt(II)

A ferrocenyl ligand was prepared from condensation of 1,1′-diacetylferrocene dihydrazone with salicylaldehyde. The ligand forms 1:1 complexes with Pd(II) and Pt(II) in good yield. Characterization of the ligand and complexes was carried out using elemental analysis, infrared study, ¹H and ¹³C nuclear magnetic resonance, and electronic absorption spectra. Anticancer activity of the prepared ligand and its complexes against human breast cancer cell line MCF-7 was determined, and the results were compared with the activity of the commonly used anticancer drug cisplatin. The results suggested that the prepared compounds possess significant antitumor activity comparable to the activity of cisplatin.     

Synthesis and biological activities of Schiff bases of gabapentin with different aldehydes and ketones: a structure–activity relationship study

A series of novel gabapentin derivatives 6a–k and 7a–f were synthesized, and their biological activities were determined. The chemical structures were confirmed by elemental analyses, UV–visible, FT-IR, and ¹H NMR spectral studies. The structure–activity relationships (SAR) for anticonvulsant and antioxidant activities were discussed. Compounds 7a–f were evaluated for their possible anticonvulsant activity by Maximal Electroshock Seizure (MES) test, and their neurotoxic effects were determined by rotorod test. Majority of the compounds were active in MES tests. Compounds 7b and 7e showed good protective effect from seizure when compared to standard drug, phenytoin (100 mg/kg). The same compounds showed no neurotoxicity at the maximum dose administered (100 mg/kg). Most of the novel compounds showed DPPH radical scavenging activity, where compounds 6f, 6j, and 7a were the best radical scavengers (IC₅₀ was about 60 μg/ml).     

Synthesis, anti-inflammatory and anticancer activity evaluation of some mono- and bis-Schiff’s bases

Several mono-Schiff’s bases (3a–i) and bis-Schiff’s bases (5a–f) were synthesized using microwave irradiation technique (3a–h, 5a–c) and by simply grinding at room temperature for a few minutes (3i, 5d–f). All these compounds were characterized by spectroscopic means and elemental analysis. They were screened for anti-inflammatory and anticancer activities (against five human cancer cell lines). Compound 5f exhibited good anti-inflammatory and compounds 3f, 5a–f exhibited good anticancer activity.     

A focus group study of patient’s perspective and experiences of type 2 diabetes and its management in Jordan

Background

Diabetes is increasingly becoming a major health problem in Jordan and glycemic goals are often not achieved.

Structure-based ensemble-QSAR model： a novel approach to the study of the EGFR tyrosine kinase and its inhibitors

Aim： To develop a novel 3D-QSAR approach for study of the epidermal growth factor receptor tyrosine kinase （EGFR TK） and its inhibi- tors. Methods： One hundred thirty nine EGFR TK inhibitors were classified into 3 clusters. Ensemble docking of these inhibitors with 19 EGFR TK crystal structures was performed. Three protein structures that showed the best recognition of each cluster were selected based on the docking results. Then, a novel QSAR （ensemble-QSAR） building method was developed based on the ligand conforma- tions determined by the corresponding protein structures. Results： Compared with the 3D-QSAR model, in which the ligand conformations were determined by a single protein structure, ensemble-QSAR exhibited higher R2 （0.87） and Q2 （0.78） values and thus appeared to be a more reliable and better predictive model. Ensemble-QSAR was also able to more accurately describe the interactions between the target and the ligands. Conclusion： The novel ensemble-QSAR model built in this study outperforms the traditional 3D-QSAR model in rationality, and provides a good example of selecting suitable protein structures for docking prediction and for building structure-based QSAR using available protein structures.     

Synthesis,characterization, and antibacterial activities of some novel N,N′-disubstituted thiourea, 2-amino thiazole,and imidazole-2-thione derivatives

In the search of bioactive molecules, a series of novel N-substituted thiourea derivatives 3(a–d) are prepared by reaction of the α-amino pyridyl ketone hydrochloride (2a) with the corresponding aryl isothiocyanates. The synthesis of some new 2-amino thiazoles 4(a–d) and imidazole-2-thiones 6(a–d) were attempted by intramolecular cyclization reaction of the N,N′-disubstituted thioureas 3(a–d) and their intermediate ketals 5(a–d) in diluted aqueous acidic and strong acidic mediums. The structure of all newly synthesized compounds was established by analytical and spectral data. The antibacterial studies to all of the synthesized compounds against Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis bacteria with Gram-positive and negative strains, as MIC values are reported. Some of these compounds such as 3a,b,d and 4b,d exhibited a good to significant antibacterial activity. Also, all of new synthesized compounds 3,4,6(a–d) were active against Gram-positive S. aureus bacterium. Thus, some of these compounds can emerge as a promising tool for further research work.     

In vitro and in vivo characterization of PF-04418948, a novel, potent and selective prostaglandin EP₂ receptor antagonist

BACKGROUND AND PURPOSE

Studies of the role of the prostaglandin EP₂ receptor) have been limited by the availability of potent and selective antagonist tools. Here we describe the in vitro/in vivo pharmacological characterization of a novel EP₂ receptor antagonist, PF-04418948 (1-(4-fluorobenzoyl)-3-{[(6-methoxy-2-naphthyl)oxy]methyl} azetidine-3-carboxylic acid).

EXPERIMENTAL APPROACH

Functional antagonist potency was assessed in cell-based systems expressing human EP₂ receptors and native tissue preparations from human, dog and mouse. The selectivity of PF-04418948 was assessed against related receptors and a panel of GPCRs, ion channels and enzymes. The ability of PF-04418948 to pharmacologically block EP₂ receptor function in vivo was tested in rats.

KEY RESULTS

PF-04418948 inhibited prostaglandin E₂ (PGE₂)-induced increase in cAMP in cells expressing EP₂ receptors with a functional K_B value of 1.8 nM. In human myometrium, PF-04418948 produced a parallel, rightward shift of the butaprost-induced inhibition of the contractions induced by electrical field stimulation with an apparent K_B of 5.4 nM. In dog bronchiole and mouse trachea, PF-04418948 produced parallel rightward shifts of the PGE₂-induced relaxation curve with a K_B of 2.5 nM and an apparent K_B of 1.3 nM respectively. Reversal of the PGE₂-induced relaxation in the mouse trachea by PF-04418948 produced an IC₅₀ value of 2.7 nM. Given orally, PF-04418948 attenuated the butaprost-induced cutaneous blood flow response in rats. PF-04418948 was selective for EP₂ receptors over homologous and unrelated receptors, enzymes and channels.

CONCLUSIONS AND IMPLICATIONS

PF-04418948 is an orally active, potent and selective surmountable EP₂ receptor antagonist that should aid further elaboration of EP₂ receptor function.

LINKED ARTICLE

This article is commented on by Birrell and Nials, pp. 1845–1846 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01494.x     

Tamoxifen-loaded nanoparticles based on a novel mixture of biodegradable polyesters: characterization and in vitro evaluation as sustained release systems

Nanoparticles (NP) from mixtures of two poly(D,L-lactide-co-caprolactone) (PLC) copolymers, PLC 40/60 and PLC 86/14, with poly(D,L-lactide) (PDLLA) and PCL were prepared: PLC 40/60-PCL (25:75), PLC 86/14-PCL (75:25) and PLC 86/14-PLA (75:25). Tamoxifen was loaded with encapsulation efficiency between 65% and 75% (29.9-36.3?μg TMX/ mg NP). All selected systems showed spherical shape and nano-scale size. TMX-loaded NPs were in the range of 293-352?nm. TMX release from NP took place with different profiles depending on polymeric composition of the particles. After 60 days, 59.81% and 82.65% of the loaded drug was released. The cytotoxicity of unloaded NP in MCF7 and HeLa cells was very low. Cell uptake of NP took place in both cell types by unspecific internalization in a time dependent process. The administration of 6 and 10?μm TMX by TMX-loaded NP was effective on both cellular types, mainly in MCF7 cells.     

Age and gender dependent bioavailability of R- and R,S-α-lipoic acid: a pilot study

Lipoic acid (LA) shows promise as a beneficial micronutrient toward improving elder health. Studies using old rats show that (R)-α-LA (R-LA) significantly increases low molecular weight antioxidants that otherwise decline with age. Despite this rationale for benefiting human health, little is known about age-associated alterations in absorption characteristics of LA, or whether the commercially available racemic mixture of LA (R,S-LA) is equally as bioavailable as the naturally occurring R-enantiomer. To address these discrepancies, a pilot study was performed to establish which form of LA is most effectively absorbed in older subjects relative to young volunteers. Young adults (average age=32 years) and older adults (average age=79 years) each received 500 mg of either R- or R,S-LA. Blood samples were collected for 3h after supplementation. After a washout period they were given the other chiral form of LA not originally ingested. Results showed that 2 out of 6 elder males exhibited greater maximal plasma LA and area under the curve for the R-form of LA versus the racemic mixture. The elder subjects also demonstrated a reduced time to reach maximal plasma LA concentration following R-LA supplementation than for the racemic mixture. In contrast, young males had a tendency for increased bioavailability of R,S-LA. Overall, bioavailability for either LA isoform was much more variable between older subjects compared to young adults. Plasma glutathione levels were not altered during the sampling period. Thus subject age, and potential for varied response, should be considered when determining an LA supplementation regimen.     

Synthesis, characterization, and antimicrobial activity of copper(II) complexes with N,N′-propanediyl-bis-benzenesulfonamide and N,N′-ethanediyl-bis-2-methylbenzenesulfonamide

Copper(II) complexes of new aryldisulfonamides (L ₁  = N,N′-bis[(2-methylphenyl)sulfonyl]ethylenediamine) and L ₂  = N,N′-propanediyl-bis-benzenesulfonamide with 1,10-phenanthroline have been synthesized and characterized by using elemental analyses, FT-IR, LCMS, conductivity, and magnetic susceptibility techniques. The structures of [Cu(phen)₂]L₁ (1) and [CuL₂(phen)₂] (2) compounds have been determined. Complex (1) has also been characterized by single crystal X-ray diffraction. The complex (1) crystallizes in the triclinic system, space group P1, with cell constants a = 12.9353(8) Å, b = 13.8543(9) Å, c = 14.4513(10) Å, α = 103.593(5)°, β = 113.713(5)°, γ = 106.104(5)°, and Z = 1. The antibacterial activities of synthesized compounds were studied against Gram-positive bacteria: Staphylococcus aureus, Bacillus subtilis, and B. cereus and Gram-negative bacteria: Escherichia coli, Pseudomonas aeruginosa, and Yersinia enterocolitica by microdilution (as MICs in μg/mL) and disk diffusion (as diameter zone in mm) method. The biological activity screening showed that (1) has more activity than (2) against the tested bacteria.     

Synthesis and characterization of a novel controlled release zinc oxide/gentamicin–chitosan composite with potential applications in wounds care

Freshly prepared ZnO nanoparticles were incorporated into a chitosan solution in weight ratios ranging from 1:1 to 12:1. Starting from the ratio of 3:1 the chitosan solution was transformed into a gel with a high consistency, which incorporates 15 mL water for only 0.1 g solid substance. The powders obtained after drying the gel were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM) and thermal analysis (TG-DSC). The electronic (UV–vis), infrared (FTIR) and photoluminescence (PL) spectra were also recorded. ZnO particles were coated with gentamicin and incorporated into the chitosan matrix, to yield a ZnO/gentamicin–chitosan gel. The release rate of gentamicin was monitored photometrically. This ZnO/gentamicin–chitosan gel proved great antimicrobial properties, inhibiting Staphylococcus aureus and Pseudomonas aeruginosa growth in both planktonic and surface-attached conditions. The results indicate that the obtained composite can be used in cutaneous healing for developing improved wound dressings, which combine the antibacterial activity of all three components with the controlled release of the antibiotic. This wound dressing maintains a moist environment at the wound interface, providing a cooling sensation and soothing effect, while slowly releasing the antibiotic. The system is fully scalable to any other soluble drug, as the entire solution remains trapped in the ZnO–chitosan gel.