New Griselimycins for Treatment of Tuberculosis

Griselimycin (GM), a natural product isolated a half century ago, is having a bit of a renaissance. After being known for more than 50 years, it is now being pursued as a treatment for tuberculosis. With the new mechanism of action, excellent in vitro and in vivo activity against sensitive and drug-resistant Mycobacterium tuberculosis, and the improved pharmacokinetic properties, the cyclohexyl derivative of GM demonstrates a high translational potential

A New Compound (8,9) -Furanyl-Pterocarpan-3-Ol Used for Standardization of Bengkuang (Pachyrhizus erosus) Extract as Sunscreen and Skin Whitening Agent

Bengkuang (Pachyrhizus erosus) has been traditionally used as sun screening and skin whitening. The active compounds in bengkuang extract already published included their activities in antioxidant and skin whitening. However, standardization of bengkuang extract has not been studied. This research aims to find out the analysis procedure by High Performance Liquid Chromatography to make standardization bengkuang extract.The first step of this research was collecting bengkuang from Prembun, Central Java, Indonesia in dry season. After cleaning and peeling, bengkuang root was sliced, dried and ground to make powder. Then followed by extraction using Soxhlet in petroleum ether and subsequently in methanol. Methanol extract was evaporated and then partitioned with ethyl acetate-water. Ethyl acetate fraction was evaporated and then separated in open column chromatography using silica gel as stationary phase and a gradient mixture of chloroform-ethyl acetate-methanol as mobile phase. Bio guided fraction method was used for separation and purification to get isolated compounds. The isolated compounds obtained from this fractionation were then elucidated and analyzed their activities.A new compound (8,9-furanyl-pterocarpan-ol) has been selected as a biomarker for extract standardization. The optimum of HPLC condition for standardization consisted of a column (Zorbax SB-C18; i.d. 0.46 cm; 5 μm particle size), mobile phase (gradient elution of MeOH-water) with flow rate of 1 ml/min and detector (UV-detector at 293 nm). The obtained LOD value was 0.51 ± 0.02 µg. The potentials of this compound to absorb UV ray, antioxidant and anti-tyrosinase were 4.018 mAU*S/mml; 2.113±0.001mM (SC50); 7.19±0.11 mM (IC50), respectively.Keywords : bengkuang (Pachyrhizus erosus) extract, (8,9)-furanyl-pterocarpan-3-ol, standardization, sunscreen, skin whitenin

Random Boolean Network Models and the Yeast Transcriptional Network

The recently measured yeast transcriptional network is analyzed in terms of simplified Boolean network models, with the aim of determining feasible rule structures, given the requirement of stable solutions of the generated Boolean networks. We find that for ensembles of generated models, those with canalyzing Boolean rules are remarkably stable, whereas those with random Boolean rules are only marginally stable. Furthermore, substantial parts of the generated networks are frozen, in the sense that they reach the same state regardless of initial state. Thus, our ensemble approach suggests that the yeast network shows highly ordered dynamics.Comment: 23 pages, 5 figure

Crystal structure of 5,11-dihydropyrido-[2,3-b][1,4]benzodiazepin-6-one

Acknowledgements The authors thank Andreas Lorbach and Todd B. Marder (Institute of Inorganic Chemistry, Wuerzburg University) for the data collection and structure solution. We appreciate the financial support provided to NMR by the Deutscher Akademischer Austauschdienst (DAAD). Thanks are also due to the Deutsche Forschungsgemeinschaft for financial support (SFB 630, Recognition, Preparation and Functional Analysis of Agents against Infectious Diseases, project A1).Peer reviewedPublisher PD

Improving anti-trypanosomal activity of alkamides isolated from Achillea fragrantissima

In previous studies the aerial parts of Achillea fragrantissima were found to have substantial antileishmanial and antitrypanosomal activity. A bioassay-guided fractionation of a dichloromethane extract yielded the isolation of the essential anti-trypanosomal compounds of the plant. Seven sesquiterpene lactones (including Achillolide-A), two flavonoids, chrysosplenol-D and chrysosplenetine, and four alkamides (including pellitorine) were identified. This is the first report for the isolation of the sesquiterpene lactones 3 and 4, chrysosplenetine and the group of alkamides from this plant. Bioevaluation against Trypanosoma brucei brucei TC221 (T.b brucei) using the Alamar-Blue assay revealed the novel alkamide 13 to have an IC50 value of 40.37 μM. A compound library, derived from the alkamide pellitorine (10), was synthesized and bioevaluated in order to find even more active substances. The most active compounds 26 and 27 showed activities in submicromolar concentrations and selectivity indices of 20.1 and 45.6, respectively, towards macrophage cell line J774.1. Toxicity of 26 and 27 was assessed using the greater wax moth Galleria mellonella larvae as an in vivo model. No significant toxicity was observed for the concentration range of 1.25–20 mM.We thank Dr. Ulrich Hildebrandt and Dr. Gerd Vogg, Botanical garden, University of Würzburg, for identifying the seeds and plants of A. fragrantissima. We are grateful to Prof. Dr. August Stich, Medical Mission Institute, University of Würzburg, for providing the respective lab facilities to perform the anti-trypanosomal assay. Many thanks for Dr. Ludwig Hoellein for proof-reading the manuscript. We wish to thank the German Academic Exchange Service (DAAD) for the doctoral scholarship of Joseph Skaf (grant number: 57169181). Srikkanth Balasubramanian was supported by a grant of the German Excellence Initiative to the Graduate School of Life Sciences, University of Würzburg

Charged aerosol detector response modeling for fatty acids based on experimental settings and molecular features: a machine learning approach

The charged aerosol detector (CAD) is the latest representative of aerosol-based detectors that generate a response independent of the analytes’ chemical structure. This study was aimed at accurately predicting the CAD response of homologous fatty acids under varying experimental conditions. Fatty acids from C12 to C18 were used as model substances due to semivolatile characterics that caused non-uniform CAD behaviour. Considering both experimental conditions and molecular descriptors, a mixed quantitative structure–property relationship (QSPR) modeling was performed using Gradient Boosted Trees (GBT ). The ensemble of 10 decisions trees (learning rate set at 0.55, the maximal depth set at 5, and the sample rate set at 1.0) was able to explain approximately 99% (Q2: 0.987, RMSE: 0.051) of the observed variance in CAD responses. Validation using an external test compound confirmed the high predic- tive ability of the model established (R2: 0.990, RMSEP: 0.050). With respect to the intrinsic attribute selection strategy, GBT used almost all independent variables during model building. Finally, it attributed the highest importance to the power function value, the flow rate of the mobile phase, evaporation temperature, the content of the organic solvent in the mobile phase and the molecular descriptors such as molecular weight (MW ), Radial Distribution Func- tion—080/weighted by mass (RDF080m) and average coefficient of the last eigenvector from distance/detour matrix (Ve2_D/Dt). The identification of the factors most relevant to the CAD responsiveness has contributed to a better understanding of the underlying mechanisms of signal generation. An increased CAD response that was obtained for acetone as organic modifier demonstrated its potential to replace the more expensive and environmentally harmful acetonitrile

Cinnamic Acid Bornyl Ester Derivatives from Valeriana wallichii Exhibit Antileishmanial In Vivo Activity in Leishmania major-Infected BALB/c Mice

Human leishmaniasis covers a broad spectrum of clinical manifestations ranging from selfhealing cutaneous leishmaniasis to severe and lethal visceral leishmaniasis caused among other species by Leishmania major or Leishmania donovani, respectively. Some drug candidates are in clinical trials to substitute current therapies, which are facing emerging drugresistance accompanied with serious side effects. Here, two cinnamic acid bornyl ester derivatives (1 and 2) were assessed for their antileishmanial activity. Good selectivity and antileishmanial activity of bornyl 3-phenylpropanoate (2) in vitro prompted the antileishmanial assessment in vivo. For this purpose, BALB/c mice were infected with Leishmania major promastigotes and treated with three doses of 50 mg/kg/day of compound 2. The treatment prevented the characteristic swelling at the site of infection and correlated with reduced parasite burden. Transmitted light microscopy and transmission electron microscopy of Leishmania major promastigotes revealed that compounds 1 and 2 induce mitochondrial swelling. Subsequent studies on Leishmania major promastigotes showed the loss of mitochondrial transmembrane potential (ΔΨm) as a putative mode of action. As the cinnamic acid bornyl ester derivatives 1 and 2 had exhibited antileishmanial activity in vitro, and compound 2 in Leishmania major-infected BALB/c mice in vivo, they can be regarded as possible lead structures for the development of new antileishmanial therapeutic approaches

Synthesis of a group of novel Xanomeline/77-LH-28-1 hybrid ligands and their FRET investigation at muscarinic acetylcholine receptor subtypes

In connection with our interest in investigating novel rationally designed bitopic (i.e., orthosteric/allosteric) derivatives targeting muscarinic acetylcholine receptor (mAChR) subtypes (1,2,3), in this study we designed and synthesized a new set of ligands that integrate in the same molecular skeleton the pharmacophoric moieties of Xanomeline and of 77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone). Xanomeline is a well-known M1/M4-preferring orthosteric agonist, which ameliorated cognitive impairments in Alzheimer\u2019s disease patients and showed activity in various models of schizophrenia, thus being potentially beneficial for treatment of positive, negative and cognitive symptoms (4). On the other hand, 77-LH-28-1 was characterized as an M1-selective, positive allosteric modulator, thus representing an interesting pharmacological tool with cognition enhancing properties (5). As illustrated below, we planned the novel bipharmacophoric derivatives as merged structures, with the tetrahydropyridine nucleus of Xanomeline as the central core. In the last years, different receptor sensors, based on the fluorescence resonance energy transfer (FRET), were generated for various G protein-coupled receptors, and represented a valuable tool to investigate real time receptor activation as well as ligand-receptor interactions. Recently, this analysis was performed also on a set of bitopic ligands designed for a selective interaction with M1 mAChRs (6). Our preliminary results on the group of Xanomeline/77-LH-28-1 hybrid compounds indicate, for the M1 sensor, a reproducible activation response, which depends on the linker length. Conversely, no FRET-related effect could be detected at the M2 sensor. Thus, a critical spacer length of the hybrid compounds induces conformational changes with a degree of selectively for the M1 muscarinic receptor. The synthesis and the results of pharmacological investigation will be presented and discussed. References: 1. J. Antony, K. Kellershohn, M. Mohr-Andr\ue4, A. Kebig, S. Prilla, M. Muth, E. Heller, T. Disingrini, C. Dallanoce et al., FASEB J 2009, 23, 442-450. 2. A. Bock, B. Chirinda, F. Krebs, R. Messerer, J. B\ue4tz, M. Muth, C. Dallanoce et al., Nat. Chem. Biol. 2014, 10, 18-20. 3. A. Bock, M. Bermudez, F. Krebs, C. Matera, B. Chirinda, D. Sydow, C. Dallanoce et al., J. Biol. Chem. 2016, 291, 16375-16389. 4. S. Barak, I. Weiner, Int. J. Neuropsychoph. 2011, 14, 1233-1246. 5. C. J. Langmead, N. E. Austin, C. L. Branch, J. T. Brown, K. A. Buchanan, C. H. Davies, I. T. Forbes et al., Br. J. Pharmacol. 2008, 154, 1104-1115. 6. R. Messerer, M. Kauk, D. Volpato, M. C. Alonso Canizal, J. Kl\uf6ckner, U. Zabel, S. Nuber, C. Hoffmann, U. Holzgrabe, ACS Chem. Biol. 2017, 12, 833-843

Ameliorative effect of mimo2 (a novel compound from Moringa oleifera leaves) against vanadium-induced neurotoxicity

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Population pharmacokinetics at two dose levels and pharmacodynamic profiling of flucloxacillin

Flucloxacillin is often used for the treatment of serious infections due to sensitive staphylococci. The pharmacokinetic (PK)-pharmacodynamic (PD) breakpoint of flucloxacillin has not been determined by the use of population PK. Targets based on the duration of non-protein-bound concentrations above the MIC (fT(> MIC)) best correlate with clinical cure rates for beta-lactams. We compared the breakpoints for flucloxacillin between several dosage regimens. In a randomized, two-way crossover study, 10 healthy volunteers received 500 mg and 1,000 mg flucloxacillin as 5-min intravenous infusions. Drug concentrations were determined by high-pressure liquid chromatography. We used the programs WinNonlin for noncompartmental analysis and statistics and NONMEM for population PK and Monte Carlo simulation. We compared the probability of target attainment (PTA) for intermittent- and continuous-dosage regimens based on the targets of fT(> MIS)s of >= 50% and >= 30% of the dosing interval. The clearance and the volume of distribution were very similar after the administration of 500 mg and 1,000 mg flucloxacillin. We estimated renal and nonrenal clearances of 5.37 liters/h (coefficient of variation, 19%) and 2.73 liters/h (33%). For near maximal killing (target, fT(> MIC) of >= 50%) flucloxacillin showed a robust (>= 90%) PTA up to MICs of 0.75 to 1 mg/liter (PTA of 860/v at 1 mg/liter) for a continuous or a prolonged infusion of 6 g/day. Short-term infusions of 6 g/day had a lower breakpoint of 0.25 to 0.375 mg/liter. The flucloxacillin PK was linear for doses of 500 mg and 1,000 mg. Prolonged and continuous infusion at a 66% lower daily dose achieved the same PK-PD breakpoints as short-term infusions. Prolonged infusion and continuous infusion are appealing options for the treatment of serious infections caused by sensitive staphylococci