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Streptococcus (S.) pneumoniae is a major cause of secondary bacterial pneumonia during influenza epidemics. Neuraminidase (NA) is a virulence factor of both pneumococci and influenza viruses. Bacterial neuraminidases (NAs) are structurally related to viral NA and susceptible to oseltamivir, an inhibitor designed to target viral NA. This prompted us to evaluate the antipneumococcal potential of two NA inhibiting natural compounds, the diarylheptanoid katsumadain A and the isoprenylated flavone artocarpin. Chemiluminescence, fluorescence-, and hemagglutination-based enzyme assays were applied to determine the inhibitory efficiency (IC(50) value) of the tested compounds towards pneumococcal NAs. The mechanism of inhibition was studied via enzyme kinetics with recombinant NanA NA. Unlike oseltamivir, which competes with the natural substrate of NA, artocarpin exhibits a mixed-type inhibition with a Ki value of 9.70 μM. Remarkably, artocarpin was the only NA inhibitor (NAI) for which an inhibitory effect on pneumococcal growth (MIC: 0.99-5.75 μM) and biofilm formation (MBIC: 1.15-2.97 μM) was observable. In addition, we discovered that the bactericidal effect of artocarpin can reduce the viability of pneumococci by a factor of >1000, without obvious harm to lung epithelial cells. This renders artocarpin a promising natural product for further investigations., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

In a previous study the simple, naturally derived coumarin scopoletin (SCT) was identified as an inhibitor of acetylcholinesterase (AChE), using a pharmacophore-based virtual screening approach. In this study the potential of SCT as procholinergic and cognition-enhancing therapeutic was investigated in a more detailed way, using different experimental approaches like measuring newly synthesized acetylcholine (ACh) in synaptosomes, long-term potentiation (LTP) experiments in hippocampal slices, and behavior studies. SCT enhanced the K+-stimulated release of ACh from rat frontal cortex synaptosomes, showing a bell-shaped dose effect curve (E(max): 4 μM). This effect was blocked by the nicotinic ACh receptor (nAChR) antagonists mecamylamine (MEC) and dihydro-β-erythroidine (DHE). The nAChR agonist (and AChE inhibitor) galantamine induced a similar increase in ACh release (E(max): 1 μM). SCT potentiated LTP in hippocampal slices of rat brain. The high-frequency stimulation (HFS)-induced, N-methyl-D-aspartate (NMDA) receptor dependent LTP of field excitatory postsynaptic potentials at CA3-CA1 synapses was greatly enhanced by pre-HFS application of SCT (4 μM for 4 min). This effect was mimicked by nicotine (2 μM) and abolished by MEC, suggesting an effect on nAChRs. SCT did not restore the total inhibition of LTP by NMDA receptor antagonist D, L-2-amino-5-phosphonopentanoic acid (AP-5). SCT (2 μg, i.c.v.) increased T-maze alternation and ameliorated novel object recognition of mice with scopolamine-induced cholinergic deficit. It also reduced age-associated deficits in object memory of 15-18-month-old mice (2 mg/kg sc). Our findings suggest that SCT possesses memory-improving properties, which are based on its direct nAChR agonistic activity. Therefore, SCT might be able to rescue impaired cholinergic functions by enhancing nAChR-mediated release of neurotransmitters and promoting neural plasticity in hippocampus., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

Since the late 1990's, novel insights into molecular biology and carcinogenesis enabled the rational design of mechanism-based anticancer therapeutics. The large number of natural product (NP)-derived drugs currently under clinical evaluation and the recent approval of temsirolimus (Torisel) as a first mTOR protein kinase inhibitor indicate that NPs have to be considered not only as a seminal source of cytotoxic, but also as a source of molecularly targeted agents. Whereas molecular modeling is well established as an important and successful method to discover and rationalize bioactivities in medicinal chemistry research, its application has also proven to be also a powerful tool in the field of NPs. This review highlights the impact of computer-assisted approaches on NPs as molecularly targeted anticancer drugs. Examples of applications are provided focusing on innovative targets such as protein kinases, tumour vasculature, epigenetic modulators, heat shock protein (Hsp) 90, and direct apoptosis enhancers.

This investigation aims to evaluate strategies for an efficient selection of bioactive compounds from the multitude and biodiversity of the plant kingdom. Statistics prove natural products (NPs) as a source leading most consistently to successful development of new drugs. However, there are several reasons why the interest in finding bioactive NPs has generally declined at several major pharmaceutical companies. Their substantial argument is that the research in this field is time-consuming, highly complex and ineffective. A more rational and economic search for new lead structures from nature must therefore be a priority in order to overcome these problems. In this paper, different strategies are described to exploit the molecular diversity of bioactive secondary metabolites, namely classical pharmacognostic approaches and computational methods. The latter include various data mining tools, like virtual screening filtering experiments using pharmacophore models, docking studies, and neural networks, which help to establish a relationship between chemical structure and biological activity. The strengths and weaknesses of these methods will be shown in this review. Focusing on selected targets within the arachidonic acid cascade (phospholipase A(2), 5-lipoxygenase, cyclooxygenase-1 and -2), several studies of successful discoveries in the field of anti-inflammatory NPs were scrutinized for the applied strategies. Both the compilation of relevant published data and recent studies supported by our own research clearly demonstrate the benefits of the synergistic effect of a hybridization of these strategies for an effective drug discovery from natural ingredients.

The aim of this study was to investigate the binary phase diagram and the polymorphism and pseudopolymorphism of racemic and enantiomeric felodipine, including their spectroscopic and thermodynamic properties. Different crystal forms were obtained by crystallization from solvents or from the annealed melt and investigated by thermal analysis (hot stage microscopy, differential scanning calorimetry, thermogravimetric analysis), spectroscopic methods (Fourier transform infrared-and Fourier transform-Raman spectroscopy), and X-ray powder diffractometry. The binary melting phase diagram was constructed based on thermoanalytical investigations of quantitative mixtures of (+)- and (+/-)-felodipine. Two polymorphic forms of racemic felodipine, mod. I (mp, approximately 145 degrees C) and mod. II (mp, approximately 135 degrees C), as well as an acetone solvate (S(Ac )) were characterized. Melting equilibria of felodipine crystal forms decrease due to thermal decomposition. Enantiomeric felodipine was found to be dimorphic (En-mod. I: mp, approximately 144 degrees C; En-mod. II: mp, approximately 133 degrees C). Evaluation of the binary system of (+)- and (-)-felodipine results in the formation of a continuous series of mixed crystals between the thermodynamically stable and higher melting modifications, mod. I and En-mod. I. Their unusual curve course, termed as Roozeboom Type 2 b, passes through a maximum in the racemic mixture and is flanked by a minimum at 20% and at 80% (+)-felodipine. From the thermodynamic parameters, racemic mod. I and II are monotropically related. In contrast to S(Ac), the thermodynamically unstable mod. II shows a considerable kinetic stability. Because its crystallization is badly reproducible, the use of mod. II is not advisable for processing. However, desolvation of S(Ac) leads to a profitable crystal shape of mod. I, representing a pseudoracemate by definition.

Three modifications of D-mannitol were produced and investigated: mod. I (mp 166.5 degrees C, heat of fusion 53.5 kJ mol(-1)), mod. II (mp 166 degrees C, heat of fusion 52.1 kJ mol(-1)), and mod. III (mp incongruent 150-158 degrees C, heat of transition, III to I 0.2 kJ mol(-1)). The measured densities are 1.490 +/- 0.000 g cm(-3) [95% confidence interval (CI)] for mod. I, 1.468 +/- 0.002 g cm(-3) (95% CI) for mod. II, and 1.499 +/- 0.004 g cm(-3) (95% CI) for mod. III. It was possible to relate the different modifications given in the literature to one of the three pure crystal forms or to mixtures of two or all three modifications. The thermodynamic relationship among the crystal forms is represented in a semi-schematic energy/temperature diagram. From these data we can conclude that mod. III is thermodynamically stable at absolute zero. It is enantiotropically related to mod. I and mod. II. FTIR and Raman spectra, differential scanning calorimetry curves, and X-ray powder patterns of these crystal forms are depicted for doubtless assignment in the future. The water uptake of the three modifications at 92% relative humidity and 25 degrees C is less than 1%. The differences of the heat capacities and the heats of solution between mod. II and III are not significant, whereas mod. I shows small significant differences compared with the other modifications. In addition, compaction studies of these crystal forms were performed by means of an instrumented hydraulic press. The results show that mod. III should have the best tableting behavior under these conditions., (Copyright 2000 Wiley-Liss, Inc.)

Differential scanning calorimetry (DSC) was used to determine the transition temperature ranges (TTR) of four types of super-elastic orthodontic nickel-titanium coil springs (Sentalloy). A knowledge of the TTR provides information on the temperature at which a NiTi wire or spring can assume superelastic properties and when this quality disappears. The spring types in this study can be distinguished from each other by their characteristic TTR during cooling and heating. For each tested spring type a characteristic TTR during heating (austenite transformation) and cooling (martensite transformation) was evaluated. The hysteresis of the transition temperature, found between cooling and heating, was 3.4-5.2 K. Depending on the spring type the austenite transformation started (As) at 9.7-17.1 degrees C and finished (Af) at 29.2-37 degrees C. The martensite transformation starting temperature (Ms) was evaluated at 32.6-25.4 degrees C, while Mf (martensite transformation finishing temperature) was 12.7-6.5 degrees C. The results show that the springs become super-elastic when the temperature increases and As is reached. They undergo a loss of super-elastic properties and a rapid decrease in force delivery when they are cooled to Mf. For the tested springs, Mf and As were found to be below room temperature. Thus, at room temperature and some degrees lower, all the tested springs exert super-elastic properties. For orthodontic treatment this means the maintenance of super-elastic behaviour, even when mouth temperature decreases to about room temperature as can occur, for example, during meals.

Three monotropically related modifications of (RS)-nitrendipine (RS-NTD) were investigated. With the aid of the optical antipodes of NTD, it was possible to construct a binary phase diagram, from which it is obvious that the thermodynamically stable mod. I of RS-NTD (mp 156-158.5 degrees C, heat of fusion 41.1 +/- 0.2 kJ mol-1) is a racemic compound, while mod. II (mp 130-134 degrees C, heat of fusion 29.4 kJ mol-1) and mod. III (mp 124-126 degrees C, heat of fusion 27.2 kJ mol-1) occur as conglomerates of different modifications of R- and S-NTD. The eutectic points (calculated) are at 150 degrees C and at 19% and 81% molar fraction of an enantiomer, respectively. Two modifications of the enantiomers are characterized (En-mod. I, thermodynamically stable form, mp 156-158 degrees C, heat of fusion 34.5 +/- 1.3 kJ mol-1 and En-mod. III, mp 121 degrees C), whereas a third modification (En-mod. II) must be hypothesized pursuant to the phase diagram (mp ca. 152 degrees C). IR spectra, DSC curves, and X-ray powder diffractograms of the different phases are described. The crystal structure of the enantiomer En-mod. I is reported (monoclinic, P2(1), density 1.346 g cm-3) and compared with the X-ray structure of the racemic compound (monoclinic, P2(1)/c, density 1.356 g cm-3). A comparison with similar studies on nimodipine has been made to emphasize the parallels to a substance of this chemical group.

N,N'-But-2-ene-1,4-diylbimorphinans 1-3 have been synthesized and pharmacologically evaluated. Bimorphinans 1 and 3 show opioid antagonist activity and preference for mu and kappa opioid receptors in mouse vas deferens and guinea pig ileum preparations.