Organometallic-based antibacterial and antifungal compounds: transition metal complexes of 1,1′-diacetylferrocene-derived thiocarbohydrazone,carbohydrazone, thiosemicarbazone and semicarbazone

Organometallic-based, 1,1′-diacetylferrocene-derived antibacterial and antifungal thiocarbohydrazone, carbohydrazone, thiosemicarbazone and semicarbazone have been prepared by condensing equimolar amount of 1,1′-diacetylferrocene with thiocarbohydrazide, carbohydrazide thiosemicarbazide and semicarbazide, respectively. These were used as ligands for the preparation of their cobalt (II), copper (II), nickel (II) and zinc (II) metal complexes. All the synthesized ligands and their complexes were characterized by IR, NMR, elemental analyses, molar conductances, magnetic moments and electronic spectral data. These synthesized compounds were screened for their antibacterial activity against Escherichia coli, Bacillus subtillis, Staphylococcus aureus, Pseudomonas aeruginosa and Salmonella typhi, and for antifungal activity against Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani and Candida glaberata using the agar-well diffusion method. All the compounds showed good antibacterial and antifungal activity which increased on coordination with the metal ions thus, introducing a novel class of organometallic-based antibacterial and antifungal agents.     

HPLC of trichothecenes — Separation of neosolaniol,NT-1 toxin,and NT-2 toxin

A high pressure liquid chromatographic (HPLC) method is described for the isolation of trichothecenes formed on moldy rice. Extraction of the cultures was followed by purification and fractionation with a C₁₈-Sep Pak cartridge. The polar fraction contained neosolaniol, 4,8-diacetoxy-12,13-epoxytrichothec-9-ene-3,15-diol (NT-1) and 4-acetoxy-12,13-epoxytrichothec-9ene-3,8,15-triol (NT-2), while in another fraction HT-2 toxin, T-2 toxin and acetyl-T-2 toxin were eluted. A high pressure liquid chromatograph equipped with a C₁₈ μ Bondapak column and an R I-detector (differential refractometer) were used for the isolation procedure.     

Identification of reactive toxicants: Structure–activity relationships for amides

A diverse series of amides were evaluated for aquatic toxicity (IGC₅₀) assessed in the Tetrahymena pyriformis population growth impairment assay and for reactivity (EC₅₀) with the model soft nucleophile thiol in the form of the cysteine residue of the tripeptide glutathione. All alkylamides along with some halo-substituted amides are well predicted by the simple hydrophobicity (log K _ow)–electrophilicity (E _lumo) response-surface model [log(IGC⁻¹ ₅₀) = 0.45(log K _ow) − 0.342(E _lumo) − 1.11]. However, 2-halo amides with the halogen at the end of the molecule and α,β-unsaturated primary amides are among those derivatives identified as being more toxic than predicted by the model. Amides, which exhibit excess toxicity, were capable of forming covalent bonds through an S_N2 displacement or a Michael addition. Moreover, only those amides exhibiting excess toxicity were reactive with thiol, suggesting that the reactivity with model nucleophiles such as the thiol group may provide a means of accurately defining reactive toxicants.     

Stressors and tasks: how and when should stressors be introduced during training for task performance in stressful situations?

Studies on the training of individuals for task performance in stressful situations have typically evaluated procedures that simultaneously expose trainees to tasks and to stressors. Such procedures might create a mutual interference of the stressor with task acquisition, or conversely, of preoccupation with task acquisition with familiarization with the stressors. Using a sample of 180 males, the present study compared a procedure that temporally separates task acquisition from exposure to stressors ("phased training") with the more typical approach which combines the two ("combined training"). The comparison was carried out under varying degrees of stressor-fidelity representation in the course of training, and under two degrees of contingency between quality of task performance and the possibility of avoiding stress. The main result indicates that phased and combined training are equally effective under conditions of noncontingency. In a contingent condition, on the other hand, phased training proves to be significantly superior.     

Amide analogs of antifungal dioxane–triazole derivatives: Synthesis and in vitro activities

A new series of triazole compounds possessing an amide-part were efficiently synthesized and their in vitro antifungal activities were investigated. The amide analogs showed excellent in vitro activity against Candida, Cryptococcus and Aspergillus species. The MICs of compound 23d against C. albicans ATCC24433, C. neoformans TIMM1855 and A. fumigatus ATCC26430 were ?0.008, 0.031 and 0.031 μg/mL, respectively, (MICs of fluconazole: 0.5, >4 and >4 μg/mL; MICs of itraconazole: 0.125, 0.25, 0.25 μg/mL). Furthermore, compound 23d was stable under acidic conditions.     

Design,synthesis and bio-evaluation of C-1 alkylated tetrahydro-β-carboline derivatives as novel antifungal lead compounds

The field of antifungal agent has become static and development of resistance by the pathogen as well as limited clinical efficacy of marketed drugs demand the constant development of new antifungals. The presence of hydrocarbon chain of specific length linked with various different heterocycles was found to be an important structural feature in various antifungal lead compounds. Based on the prominent antimicrobial activity of β-carboline derivatives, a set of C1 alkylated tetrahydro-β-carboline derivatives were proposed to be active against fungi. To validate and confirm the role of suitable alkyl chains linked to a β-carboline scaffold, few related analogues having C1 aryl substituents were also synthesized in one step via classic Pictet-Spengler reaction. The synthesized library was evaluated for its antifungal activity against C. albicans, C. krusei, C. parapsilosis, C. kefyr, C. glabrata, C. tropicalis and C. neoformans. One of the library members (compound 12c), with n-alkyl chain of eight carbons exhibited potent antifungal activity against C. glabrata and C. kefyr. The lead compound, being selectively toxic also demonstrated prominent synergy enhancing the potency of antifungal drugs up to 10-fold. The time kill kinetic studies confirmed the efficacy of compound 12c, where the results obtained were comparable to that of Amp B. FE-SEM analysis revealed the increased asymmetry, disintegration and roughness of cell surface which could be because of the possible interaction of compound 12c at membrane level or interference in cell wall structure. Apoptosis/necrosis detection assay confirmed the significant apoptotic activity in C. glabrata cells after 12c treatment which was responsible for the rapid killing of C. glabrata cells.     

Advanced oxidation protein products (AOPP): novel uremic toxins, or components of the non-enzymatic antioxidant system of the plasma proteome?

In 1996, a novel oxidative stress biomarker, referred to as advanced oxidation protein products (AOPP), was detected in the plasma of chronic uremic patients. It was suggested that AOPP measure highly oxidized proteins, especially albumin. Recent data in turn appear to indicate that oxidized fibrinogen is the key molecule responsible for the AOPP reaction in the human plasma. Since fibrinogen is an acute-phase reactant, it is evident that during each episode of inflammatory response, the antioxidant capacity of the plasma is enhanced. In this context, fibrinogen can be regarded as a component of the antioxidant system of the plasma proteome. It was also demonstrated that oxidized fibrinogen is bound to apolipoprotein(a) of lipoprotein(a) via lysine binding sites. Thus, apo(a) could compete with plasminogen (and/or tissue plasminogen activator) for its binding sites of fibrin(ogen), causing inhibition of fibrinolysis, and thereby promote atherosclerosis and cardiovascular disease.     

Structure–activity relationships of tulipalines,tuliposides, and related compounds as inhibitors of MurA

The enzyme MurA performs an essential step in peptidoglycan biosynthesis and is therefore a target for the discovery of novel antibacterial compounds. We report here the inhibition of MurA by natural products from tulips (tulipalines and tuliposides), and the structure–activity relationships of various derivatives. The inhibition of MurA can be related to antibacterial activity, and MurA is probably one of the relevant molecular targets of the tulipaline derivatives. MurA inhibition by this class of compounds depends on the presence of the substrate UNAG, which indicates non-covalent suicide inhibition as observed previously for cnicin. With respect to selectivity, however, the reactivity against arbitrary sulfhydryl groups, such as in glutathione, could not yet be sufficiently separated from MurA inhibition in the present dataset.     

Bis(N-amidinohydrazones) and N-(amidino)-N′-aryl-bishydrazones: New classes of antibacterial/antifungal agents

The emergence of multidrug-resistant bacterial and fungal strains poses a threat to human health that requires the design and synthesis of new classes of antimicrobial agents. We evaluated bis(N-amidinohydrazones) and N-(amidino)-N′-aryl-bishydrazones for their antibacterial and antifungal activities against panels of Gram-positive/Gram-negative bacteria as well as fungi. We investigated their potential to develop resistance against both bacteria and fungi by a multi-step resistance-selection method, explored their potential to induce the production of reactive oxygen species, and assessed their toxicity. In summary, we found that these compounds exhibited broad-spectrum antibacterial and antifungal activities against most of the tested strains with minimum inhibitory concentration (MIC) values ranging from <0.5 to >500 μM against bacteria and 1.0 to >31.3 μg/mL against fungi; and in most cases, they exhibited either superior or similar antimicrobial activity compared to those of the standard drugs used in the clinic. We also observed minimal emergence of drug resistance to these newly synthesized compounds by bacteria and fungi even after 15 passages, and we found weak to moderate inhibition of the human Ether-à-go-go-related gene (hERG) channel with acceptable IC₅₀ values ranging from 1.12 to 3.29 μM. Overall, these studies show that bis(N-amidinohydrazones) and N-(amidino)-N′-aryl-bishydrazones are potentially promising scaffolds for the discovery of novel antibacterial and antifungal agents.     

Marine pharmacology in 2005–6: Marine compounds with anthelmintic,antibacterial, anticoagulant,antifungal, anti-inflammatory,antimalarial, antiprotozoal,antituberculosis, and antiviral activities; affecting the cardiovascular,immune and nervous systems,and other miscellaneous mechanisms of action

Background

The review presents the 2005–2006 peer-reviewed marine pharmacology literature, and follows a similar format to the authors' 1998–2004 reviews. The preclinical pharmacology of chemically characterized marine compounds isolated from marine animals, algae, fungi and bacteria is systematically presented.

Results

Anthelmintic, antibacterial, anticoagulant, antifungal, antimalarial, antiprotozoal, antituberculosis and antiviral activities were reported for 78 marine chemicals. Additionally 47 marine compounds were reported to affect the cardiovascular, immune and nervous system as well as possess anti-inflammatory effects. Finally, 58 marine compounds were shown to bind to a variety of molecular targets, and thus could potentially contribute to several pharmacological classes.

Conclusions

Marine pharmacology research during 2005–2006 was truly global in nature, involving investigators from 32 countries, and the United States, and contributed 183 marine chemical leads to the research pipeline aimed at the discovery of novel therapeutic agents.

General significance

Continued preclinical and clinical research with marine natural products demonstrating a broad spectrum of pharmacological activity will probably result in novel therapeutic agents for the treatment of multiple disease categories.     

Behavioral and Endocrine Consequences of Simultaneous Exposure to Two Different Stressors in Rats: Interaction or Independence?

Although behavioral and endocrine consequences of acute exposure to stressors have been extensively studied, little is known about how simultaneous exposure to two different stressors interacts to induce short- and long-term effects. In the present experiment we studied this interaction in adult male rats exposed to cat fur odor (impregnated cloth) or immobilization on boards either separately or simultaneously. We reasoned that exposure to the odor of a potential predator while immobilized, may potentiate its negative consequences as compared to exposure to only one of the stressors. Exposure to cat odor elicited the expected reduction of activity and avoidance of the area where the impregnated cloth was located. The endocrine response (plasma levels of ACTH and corticosterone, as a measure of the hypothalamic-pituitary-adrenal axis, HPA) was markedly greater after immobilization than after cat fur odor and no additive effects were found by simultaneous exposure to both stressors. Cat odor, but not immobilization, increased anxiety-like behavior as evaluated in the elevated plus-maze 7 days after the stressors, with no evidence of enhanced HPA activation. In addition, cat odor exposure resulted in long-lasting (8 days later) fear conditioning to the box containing a clean cloth, which was reflected by hypoactivity, avoidance of the cloth area and enhanced HPA activation. All these effects were similarly observed in rats exposed simultaneously to cat odor and immobilization. In rats only exposed to immobilization, only some weak behavioral signs of fear conditioning were found, but HPA activation in response to the context paired to immobilization was enhanced to the same extent as in cat odor-exposed animals, supporting a certain degree of endocrine conditioning. The present results did not reveal important behavioral interactions between the two stressors when animals experienced both simultaneously, whereas some interactions were found regarding HPA activation. Theoretical implications are discussed.     

A quantitative structure–antifungal activity relationship study of oxygenated aromatic essential oil compounds using data structuring and PLS regression analysis

Twenty two oxygenated aromatic essential oil compounds were chosen for the study of the antifungal activity against two wood-decaying fungi, the white-rot Trametes versicolor, which mainly metabolizes lignin, and the brown-rot Coniophoha puteana, which digests cellulose in plant cell walls. Minimal inhibitory concentrations (MICs) were determined by the agar dilution method, using dimethyl sulfoxide (DMSO) as the solvent for the selected compounds and potato-dextrose agar (PDA) as the growth medium for both fungi. The MICs were then used to generate a tree structure, which represents the structuring of the essential oil compounds by the nature and position of the substituents in their aromatic rings, and as dependent variables (log(1/MIC)) in the QSAR analysis. Data structuring proved that a relationship between the molecular structures of the essential oil compounds and their antifungal activity exists, and the hypotheses derived therefrom were complemented by performing a QSAR analysis using the partial least squares (PLS) method. Statistically significant PLS models were obtained with the 1-octanol–water partition coefficient (C log P), the energy of the highest occupied molecular orbital (E _HOMO), and the number of hydrogen-bond donor atoms in the molecules of the compounds studied (Donor) for T. versicolor and with C log P and the fractional negative surface area (FNSA1) for C. puteana.Figure Tree structure representing the structuring of the oxygenated aromatic essential-oil compounds by the position and nature of their substituents in the aromatic ring     

Isolation of antiplasmodial anthraquinones from Kniphofia ensifolia,and synthesis and structure–activity relationships of related compounds

Bioassay-guided separation of the South African plant Kniphofia ensifolia for antiplasmodial activity led to the isolation of two new anthraquinones, named kniphofiones A and B (3 and 4), together with three known bioactive anthraquinone monomers (1, 2 and 5), and four known bisanthraquinones (6–9). The structures of the two new compounds were elucidated based on analyses of their 1D and 2D NMR spectra and mass spectrometric data. The dimeric compounds 6 and 7 displayed the strongest antiplasmodial activity among all the isolated compounds, with IC₅₀ values of 0.4 ± 0.1 and 0.2 ± 0.1 μM, respectively. The two new compounds displayed modest activities, with IC₅₀ values of 26 ± 4 and 9 ± 1 μM, respectively. Due to the synthetic accessibility of the new compounds and the increased activity shown by the dimeric compounds, a structure–activity relationship study was conducted. As a result, one analogue of kniphofione B (4), the caffeic acid derivative of aloe-emodin, was found to have the highest activity among all the aloe-emodin derivatives, with an IC₅₀ value of 1.3 ± 0.2 μM.     

Synthesis and structures of three,four, and six-coordinate monomeric tin(II) and tin(IV) compounds containing η2-ketiminate ligands

A series of Sn(II) and Sn(IV) compounds containing ketiminate ligands were synthesized. Reactions of SnCl₂ with 1 or 2 equiv. Li[OCMeCHCMeNAr] (where Ar = 2,6-diisopropylphenyl) generate [OCMeCHCMeNAr]SnCl (1) and [OCMeCHCMeNAr]₂Sn (2) in moderate yield, respectively. Similarly, reacting SnCl₄ with 2 equiv. Li[OCMeCHCMeNAr] yields a six-coordinated [OCMeCHCMeNAr]₂SnCl₂ (3). Divalent tin compound 2 can be oxidized with I₂ in diethyl ether to generate tetravalent tin compound [OCMeCHCMeNAr]₂SnI₂ (4) in moderate yield. Compounds 1–4 have been characterized by ¹H and ¹³C NMR spectroscopy and have been analyzed by X-ray crystallography. Theoretical calculation found that the bonding of ketiminate ligands and tin atom in compound 2 has a strong ionic character.     

The groove assay for quantitative estimating the killer toxin activity or susceptibility of S. cerevisiae strains to killer toxins

The sensitivity of commonly used well assay for estimating the killer toxin activity or susceptibility of sensitive yeast strains to the killer toxin treatment was markedly increased by growth retardation of sensitive cells in the initial phase of the assay by using a high osmolarity medium and/or low temperature. Further improvement can be reached by channeling the diffusion of the toxin molecules from the well to the groove filled with agar medium that contains sensitive cells.     

Rediscovery of known natural compounds: nuisance or goldmine?

Do all natural compounds have a distinct biological activity, or are most of them merely biosynthetic debris? Many natural compounds have important biological functions, and certainly many more of the ample 200,000 currently known will ultimately prove to be more than just 'secondary metabolites'. The question is how to select the most promising candidates for potential new drugs. 'Rediscovery' of known natural compounds is regarded as a nuisance or disappointment by scientists involved with the identification of novel compounds. The other side of the coin, however, is that the discovery that a particular compound occurs in unrelated species can be a valuable clue toward the identification of a novel receptor or enzyme. Here, we put forward the hypothesis that when a natural compound occurs in unrelated species, it must have an important biological function by interacting with a specific molecular target. This is because it is extremely improbable that in nature one particular compound is synthesized in totally unrelated species for no reason at all. For many compounds occurring in unrelated species, it is already known that they act on specific molecular targets. For others, it is just known that they occur in different species. In some cases, biological activities are known but not the underlying mechanisms of action. It is from this category of compounds that important discoveries are likely to be made. Some (around 70) of them were identified. They represent important clues from nature offering an alternative approach to the classical screening of large numbers of compounds.     

Dose-dependent Incorporation of Tea Catechins, (–)-Epigallocatechin-3-gallate and (–)-Epigallocatechin,into Human Plasma

Tea catechins, (–)-epigallocatechin-3-gallate (EGCg) and (–)-epigallocatechin (EGC), have been reported to suppress oxidation of plasma low density lipoprotein (LDL) in vitro. If dietary catechins can be efficiently incorporated into human blood plasma, anti-atherosclerotic effects in preventing oxidative modification of LDL would be expected. In this study, a newly developed chemiluminescence detection-high pressure liquid chromatography (CL-HPLC) method for measuring plasma catechins was used and the incorporation of EGCg and EGC into human plasma was investigated. Healthy subjects orally ingested 3, 5, or 7 capsules of green tea extract (corresponding to 225, 375, and 525 mg EGCg and 7.5, 12.5, and 17.5 mg EGC, respectively). The plasma EGCg and EGC concentrations before the administration were all below the detection limit (< 2 pmol/ml), but 90 min after, significantly and dose-dependently increased to 657, 4300, and 4410 pmol EGCg/ml, and 35, 144, and 255 pmol EGC/ml, in the subjects who received 3, 5, and 7 capsules, respectively. Both EGCg and EGC levels detected in plasma corresponded to 0.2–2.0% of the ingested amount. Catechin intake had no effect on the basal level of endogenous antioxidants (α-tocopherol, β-carotene, and lycopene) or of lipids in plasma. These results suggested that drinking green tea daily would contribute to maintain plasma catechin levels sufficient to exert antioxidant activity against oxidative modification of lipoproteins in blood circulation systems.     

Volatile compounds of β-diketonates of dioxouranium(VI) with tetrahydropyran and tetrahydrothiophene

Complexes of the type [UO₂(β-diket)₂·nB] where β-diket=CF₃COCHCOR (R=CF₃, CH₃, C₄H₃S or C₆H₅ and denoted by HFAA, TFAA, TTA or BTA, respectively), B=tetrahydropyran (THP) and tetrahydrothiophene (THT) and n= 0.5–2.0, have been synthesized and characterised by infrared, ¹H NMR and mass spectral techniques. Vapour pressure of UO₂(HFAA)₂·THP was measured by the transpiration method between the temperature range of 323–391 K. The enthalpy of vaporisation of UO₂(HFAA)₂·THP was estimated to be 18.4 kcal/mol.