Structural features determining the antibiotic potencies of natural and synthetic hop bitter resins, their precursors and derivatives

Twenty-six hop bitter resins, some hitherto not investigated, were tested for antimicrobial activities. Gram-positive bacteria were much more sensitive than Gram-negative ones. The inhibitory effect against Bacillus subtilis 168 was measured by several methods and the general rule could be established that the antibiotic properties are mainly dependent on the hydrophobic parts of the molecules. Thus the acyl-lupuphenones (2-acyl-3,5-4,4',6-tri(3-methyl-2-butenyl)-cyclohexane-triones (1, 3, 5) having three prenyl and one acyl side chain are the most active substances. Their minimum inhibitory concentration (MIC) increases from the capro (0.5 muM) to the aceto derivative (11 muM). Any substitution with hydrophilic functions or loss of hydrophobic groups causes reductions in biological activity. This is most evident with the corresponding acyl-phloroglucine precursors (2-acyl-1,3,5-trihydroxybenzenes) which lack the three prenyl side chains (MIC, 110 to 5050 muM respectively). Conversion of the central six-membered ring structure into a five-membered one results in additional losses of antimicrobial activity. These findings support the proposal that the lipophilic region of the cell membrane represents the target site for the hop bitter resins.     

Characterization of acyl-ACP thioesterases of mangosteen (Garcinia mangostana) seed and high levels of stearate production in transgenic canola

Acyl-acyl-carrier protein (ACP) thioesterases are, at least in part, responsible for the fatty acyl chain length composition of seed storage oils. Acyl-ACP thioesterases with specificity for each of the saturated acyl-ACP substrates from 8:0 through 16:0 have been cloned, with the exception of 18:0, and are members of the FatB class of thioesterases. The authors have determined that the tropical tree species mangosteen (Garcinia mangostana) stores 18:0 (stearate) in its seed oil in amounts of up to 56% by weight. Acyl-ACP thioesterase activity as measured in crude mangosteen seed extracts showed a preference for 18:1-ACP substrates, but had significant activity with 18:0 relative to that with 16:0-ACP, suggesting a thioesterase might be involved in the production of stearate. Three distinct acyl-ACP thioesterases were cloned from mangosteen seed cDNA; two representative of the FatA class and one representative of the FatB class. When expressed in vitro, the enzyme encoded by one of the FatAs (Garm FatA1) while preferring 18:1-ACP showed relatively low activity with 16:0-ACP as compared to 18:0-ACP, similar to the substrate preferences shown by the crude seed extract. Expression of Garm FatA1 in Brassica seeds led to the accumulation of stearate up to 22% in seed oil. These results suggest that Garm FatA1 is at least partially responsible for determining the high stearate composition of mangosteen seed oil and that FatA as well FatB thioesterases have evolved for specialized roles.     

In vitro antimalarial activity of chalcones and their derivatives

A series of chalcones and their derivatives have been synthesized and identified as novel potential antimalarials using both molecular modeling and in vitro testing against the intact parasite. A large number of chalcones and their derivatives were prepared using one-step Claisen-Schmidt condensations of aldehydes with methyl ketones. These condensates were screened in vitro against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum and shown to be active at concentrations in the nanomolar range. The most active chalcone derivative, 1-(2,5-dichlorophenyl)-3-(4-quinolinyl)-2-propen-1-one (7), had an IC50 value of 200 nM against both a chloroquine-resistant strain (W2) and a chloroquine-sensitive strain (D6). The resistance indexes for all compounds were substantially lower than for chloroquine, suggesting that this series will be active against chloroquine-resistant malaria. Structure-activity relationships (SAR) of the chalcones in the context of a homology-based model structure of the malaria trophozoite cysteine protease, the most likely target enzyme, are presented.     

Fungitoxic activity of some cytochalasins and their derivatives on Phytophthora species

The activity of cytochalasin B was tested on 8 Phytophthora species, while the same toxin, some of its derivatives and natural analogues, namely cytochalasin F and deoxaphomin, were assayed at 2 x 10(-5) - 2 x 10(-4) M on the most sensitive species, P. cactorum. A significant inhibitory activity on P. cactorum was shown by cytochalasin B, its 7-monoacetyl derivative, and deoxaphomin. The hydroxy group at C-20 and the conformational freedom of the macrocyclic ring proved to be important structural features for this activity. The 7-hydroxy group at C-7 appeared to have no influence on this toxicity, while a size reduction associated with the carbocyclic nature of the macrocycle seems to lightly increase the activity. The 7-O-acetylcytochalasin B showed selective toxic activity on P. cactorum at the tested concentration, thus suggesting a possible use as a fungicide for this compound.     

Synthesis of some chroman derivatives and preliminary investigation on their vasodilatory activity

In this study, some N'-(chroman-4-yliden)-4-aryl-2-thiazolylhidrazide derivatives were synthesized. Their structures were elucidated by IR, NMR and microanalyses. The vasodilatory activities of the compounds obtained were examined in vitro.     

Synthesis of 5-substituted quinazolinone derivatives and their inhibitory activity in vitro

Quinazolinone derivatives I and their methyl esters were synthesized and evaluated as nonclassical lipophilic inhibitors of thymidylate synthase. Compounds Ib and Ic containing OH and CO2H as R substituents, respectively, were most effective, indicating that hydrogen bonding may contribute to the increased inhibitory activity. These compounds further showed high cytotoxic activity against tumor cells in culture.     

Photoprotective actions of natural and synthetic melanins

Melanins are thought to be important modulators of photochemistry in skin. Eumelanin, a black-brown pigment, is believed to protect against UV-induced photodamage, whereas pheomelanin, a red-yellow pigment, is believed to possess photosensitizing properties. To investigate the hypothesized dichotomy of melanins as both photoprotectants and photosensitizers, we examined the effects of melanins on UV-induced liposomal lipid peroxidation. Sepia melanin, a representative eumelanin, and both red hair pheomelanin and synthetic pheomelanin were employed in these studies. Both eumelanin and pheomelanin inhibited UVA/B- and UVA-induced liposomal lipid peroxidation in a concentration-dependent manner as measured by inhibition of conjugated diene formation. No change in protective properties of the melanins was observed in the presence of saturating levels of O2 during UVA irradiation. Pheomelanin irradiated with UVA/B or UVA induced superoxide-catalyzed reduction of nitroblue tetrazolium, whereas eumelanin did not. Melanins are known to bind various metals, and we examined the effect of iron on the photoproperties of melanins. Eumelanin complexed with Fe(III) did not inhibit UVA/B-induced lipid peroxidation, whereas pheomelanin complexed with Fe(III) stimulated UVA/B-induced lipid peroxidation. Thus, complexation with iron reversed the antioxidant effect of eumelanin and converted pheomelanin into a prooxidant. Analysis of lipid peroxidation products indicated that the oxidation was mediated by free radicals rather than by singlet oxygen. These data indicate that both eumelanin and pheomelanin exert antioxidant effects against UV-induced lipid peroxidation but that the prooxidant activities of pheomelanin result from pheomelanin-metal complexation.     

Synthesis of N-aryl-N'-heteroaryl-substituted urea and thiourea derivatives and evaluation of their anticonvulsant activity

Starting from amino(di)azines and 2-chloro-6-methyliso(thio)cyanate a series of aryl-substituted urea and thiourea derivatives was prepared and screened as potential antiepileptics. Among the new derivatives tested, only 2b and 3c exhibited adequate anticonvulsant effects, whereas 3d and 4d were found to be convulsants per se.     

Anticholinergic activity in mice and receptor-binding properties in rats of a series of synthetic tropane derivatives

AlF4- has long been known to associate with and activate the GDP-bound alpha subunits of heterotrimeric G-proteins. Recently the small guanine nucleotide binding protein Ras has also been shown to associate with AlF4- in the presence of stoichiometric amounts of its GTPase activating protein (GAP). Here we present the isolation of a stable Ras x GDP- x AlF4- x GAP ternary complex by gel filtration. In addition, we generalise the association of AlF4- with the small GTP-binding proteins by demonstrating ternary complex formation for the Cdc42, Rap and Ran proteins in the presence of their respective GAP proteins.     

Antimicrobial activity of 8-alkyl- and 8-phenyl-substituted berberines and their 12-bromo derivatives

The 8-alkyl- (3-6), 8-phenyl- (7), 12-bromo- (8), 8-alkyl-12-bromo- (9-12), and 12-bromo-8-phenyl- (13) berberine derivatives were prepared and tested for their antimicrobial activity in vitro to evaluate structure-activity relationships. Introduction of the alkyl or phenyl group and the bromine atom into the C-8 and C-12 positions of berberine (1), respectively, led to significant increases of the antimicrobial activity. In both the 8-alkyl- and 8-alkyl-12-bromo-berberines (3-6 and 9-12, respectively), the antibacterial activity increased as the length of the aliphatic chain increased. The exception was the activity against Candida albicans and Escherichia coli, which did not always increase as the alkyl side chain lengthened. Among the compounds tested, 12-bromo-8-n-hexylberberine (12) was 64, 256, 128, 16, and 32 times more active against Staphylococcus aureus, Bacillus subtilis, Salmonella enteritidis, E. coli, and C. albicans, respectively, in comparison to the clinically used berberine. Compound 12 was also found to be 8, 16, and 128 times more active against S. aureus, S. enteritidis, and C.albicans, respectively, than kanamycin sulfate, but was of the same order of activity against B. subtilis, and only one-fourth as active against E. coli.     

Correlation between the antiarrhythmic activity of acyl derivatives of phenothiazine and their affinity for phospholipid membranes

The interaction of thirteen antiarrhythmic active phenothiazine 10-acylaminopropionil derivatives with artificial phospholipid membranes was studied. Blinding constant (K) of this interaction was determined by means of a fluorescent probe. There was found a valid correlation between K and antiarrhythmic activity (A) for 10 substances; the greater the K--the greater the A. Three substances characterized by the greatest K had, however, a low A. It can be assumed that the interaction of antiarrhythmic drugs with phospholipids of target membranes in vivo is an important element of the molecular mechanism of action. At the same time a very high affinity to lipids can possibly cause a delocalization of the drug in the organism and a decrease of its antiarrhythmic activity.     

Expression of different lipoprotein receptors in natural killer cells and their effect on natural killer proliferative and cytotoxic activity

Natural killer (NK) cells take up chylomicrons (CM), very low density (VLDL), low density (LDL), high density (HDL) and acetyl-modified low density (AcLDL) lipoproteins through different receptors, VLDL being the lipoprotein with the highest uptake and HDL the lowest. The uptake of LDL can be selectively blocked by the anti-LDL receptor, which does not affect the uptake of CM, VLDL, HDL and AcLDL. Although the uptake of lipoproteins assessed by flow cytometry using DiI is not very high, the lipoproteins are able to induce an increase in proliferative responses, VLDL, AcLDL and HDL being the most important ones with 12- and 17-fold increments, respectively. CM, VLDL and LDL at low concentrations increase NK cytotoxic activity, while HDL and AcLDL inhibit, in a dose-dependent fashion, the killing of NK cells against K562. These results suggest the presence of four different receptors that are responsible for the cytotoxic and proliferative responses observed.     

Thermoluminescence characterization of natural and synthetic irradiated Ce-monazites

The thermoluminescence(TL) emission of synthetic and natural Ce-monazites was characterized here to determine the potential application in the identification of microscopic defects from a qualitative point of view trying to link each TL peak to a chemical-physical process.The kinetic parameters that lead the luminescence processes were calculated by means of variable heating rate and computing glow curve deconvolution methods and allow identifying three groups of components at ～90, 130 and 290℃(...     

Synthesis and antifungal activity of novel thiazole-containing triazole antifungals

A new series of thiazole-containing triazole antifungals was synthesized and evaluated for antifungal activity against a variety of clinically isolated pathogenic fungi in vitro and against systemic candidosis in vivo. Among these compounds, (+/-)-1-(2,4-difluorophenyl)-1-[4-(2,4-difluorophenyl) thiazol-2-yl]-2-(1H-1,2,4-triazol-1-yl)ethanol (ER24161) showed the most potent and well-balanced in vitro activities and excellent in vivo efficacy. We also achieved an enantioselective synthesis of the more potent enantiomer of ER-24161.     

A comparative study on physicochemical properties of hydroxyapatite powders derived from natural and synthetic sources

Hydroxy apatite (HA) is effectively used as a bioimplant material because it closely resembles bone apatite and exhibits good biocompatibility. So, in this research, HA powders were produced by calcinations of natural bones including human, bovine, camel and horse bones, and also via sol-gel method. Powders characterizations of natural HA and Synthetic HA were studied by X-ray powder diffraction (XRD), X-ray fluorescence (XRF), Fourier transform infrared (FTIR) and scanning electron microscopy (SEM), combined with transmission electron microscopy (ТЕМ). In order to verify the biocompatibility of these HA powders, MTT assay was applied. The XRD results showed that the HA powders were successfully produced by using different sources. Also, it was obvious from XRF analysis that the main components of them were Ca and P. Furthermore, it was seen that the size of particles was in the nanometric scale and they showed agglomerates consisting of numerous nanocrystals. FTIR spectra of all samples proved the presence of various CO ₃ ^2- , PO ₄ ^3- and OH^– groups in the powders. In addition, the MTT assay revealed that the cells proliferations in the presence of horse and human HA nanopowders were stimulated.     

Solid phase organic synthesis of polyamine derivatives and initial biological evaluation of their antitumoral activity

The hyperpolarization-activated inward current (If) has been discussed to contribute to arrhythmias in human atrial myocardium. If was found to be increased by beta-adrenergic stimulation. In the present study, we evaluate the modulation of If by carbachol, adenosine and by class Ic, III and IV antiarrhythmic drugs in isolated human atrial myocytes. The whole-cell patch-clamp technique was used to record If in isolated myocytes from 18 human right atrial appendages. A typical time- and voltage-dependent hyperpolarization-activated inward current could be recorded in all cells investigated (n=56). Mean current density recorded at -130 mV was -2.8+/-1.2 pApF(-1). Both adenosine and carbachol were found to directly inhibit If in human atrial myocytes by shifting the activation curves to more negative potentials. Adenosine 10(-5) mol/l shifted the potential of half-maximal activation by -5.9+/-0.4 mV from -99.4+/-0.6 mV to -105.3+/-0.4 mV (n=8; P<0.05), and carbachol 10(-5) mol/l by -5.7+/-0.5 mV from -99.2+/-0.5 mV to -104.9+/-0.6 mV (n=6; P<0.05). The concentration-response curve of adenosine calculated by a Hill function yielded a half-maximal effect of adenosine (EC50) at a concentration of 3.6+/-0.5 micromol/l, a maximal shift of -6.5+/-0.3 mV, and a Hill coefficient (h) of 2.40. We did not observe any effect of flecainide (10(-5) mol/l; n=8), sotalol (10(-5) mol/l; n=6), amiodarone (10(-5) mol/l; n=6) or verapamil (10(-5) mol/l; n=5) on If in human atrial myocytes. However, propafenone (10(-5) mol/l) was found to reversibly reduce If current size (9/13 cells) by shifting the activation curve by -5.2+/-0.4 mV (P<0.05). In human atria adenosine- and muscarinic receptor stimulation might function as endogenous protective mechanisms inhibiting the initiation of ectopic tachycardia by reducing If current size. Propafenone may be more effective in some patients with atrial tachycardias that do not respond to other class Ic, III and IV antiarrhythmic drugs. However, it has yet to be defined whether these agents suppress atrial tachycardias via an inhibition of If in vivo.     

Growth medium effect on the antifungal activity of LY 303366

The incidence of circumcision in 256 pregnant Nigerian Igbo women was 124 (48.4%). This incidence increased with increasing social class (circumcision index (C.I), 0.06 to 16.50, for social class 1 to 5); was least among the least age range, 16-20 years (C.I, 0.45); and among the primigravidae (C.I, 0.36) compared to the grandmultipara (C.I, 4.43) (P < 0.05.). Simple excision was the commonest type of circumcision, 122 (98.4%). The genital introitus was mildly scarred in 48 (38.7%) respondents, moderately scarred in 47 (37.9%) and severely scarred in 29 (23.4%). Ninety four (36.7%) of the respondents were not aware of their circumcision status, while 91 (96.8%) of the circumcised women had it performed during infancy. On the question of continued practice of female circumcision in their villages, 43 (16.8%) respondents replied, "yes"; 138 (53.9%), "no"; 25 (9.8%) "Sometimes"; and 50 (19.5%), "don't know". The incidence of episiotomy during delivery was similar for both circumcised, 47 (18.4%)and uncircumcised, 46 (18.0%) respondents (P = 0.05). More uncircumcised respondents, 31 (12.1%) were sexually satisfied during intercourse than the circumcised, 11 (4.3%) (P < 0.05). Of the 118 female offsprings of the respondents, 109 (92.4%) were not circumcised while 9 (7.6%) were. Increased public enlightenment on the risks of female circumcision is expected to eradicate the practice by the next generation