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

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

A New Bioactive Compound From the Marine Sponge-Derived Streptomyces sp. SBT348 Inhibits Staphylococcal Growth and Biofilm Formation

Staphylococcus epidermidis, the common inhabitant of human skin and mucosal surfaces has emerged as an important pathogen in patients carrying surgical implants and medical devices. Entering the body via surgical sites and colonizing the medical devices through formation of multi-layered biofilms leads to refractory and persistent device-related infections (DRIs). Staphylococci organized in biofilms are more tolerant to antibiotics and immune responses, and thus are difficult-to-treat. The consequent morbidity and mortality, and economic losses in health care systems has strongly necessitated the need for development of new anti-bacterial and anti-biofilm-based therapeutics. In this study, we describe the biological activity of a marine sponge-derived Streptomyces sp. SBT348 extract in restraining staphylococcal growth and biofilm formation on polystyrene, glass, medically relevant titan metal, and silicone surfaces. A bioassay-guided fractionation was performed to isolate the active compound (SKC3) from the crude SBT348 extract. Our results demonstrated that SKC3 effectively inhibits the growth (MIC: 31.25 μg/ml) and biofilm formation (sub-MIC range: 1.95–<31.25 μg/ml) of S. epidermidis RP62A in vitro. Chemical characterization of SKC3 by heat and enzyme treatments, and mass spectrometry (HRMS) revealed its heat-stable and non-proteinaceous nature, and high molecular weight (1258.3 Da). Cytotoxicity profiling of SKC3 in vitro on mouse fibroblast (NIH/3T3) and macrophage (J774.1) cell lines, and in vivo on the greater wax moth larvae Galleria mellonella revealed its non-toxic nature at the effective dose. Transcriptome analysis of SKC3 treated S. epidermidis RP62A has further unmasked its negative effect on central metabolism such as carbon flux as well as, amino acid, lipid, and energy metabolism. Taken together, these findings suggest a potential of SKC3 as a putative drug to prevent staphylococcal DRIs

Modeling antibiotic and cytotoxic effects of the dimeric isoquinoline IQ-143 on metabolism and its regulation in Staphylococcus aureus, Staphylococcus epidermidis and human cells

Background: Xenobiotics represent an environmental stress and as such are a source for antibiotics, including the isoquinoline (IQ) compound IQ-143. Here, we demonstrate the utility of complementary analysis of both host and pathogen datasets in assessing bacterial adaptation to IQ-143, a synthetic analog of the novel type N,C-coupled naphthyl-isoquinoline alkaloid ancisheynine. Results: Metabolite measurements, gene expression data and functional assays were combined with metabolic modeling to assess the effects of IQ-143 on Staphylococcus aureus, Staphylococcus epidermidis and human cell lines, as a potential paradigm for novel antibiotics. Genome annotation and PCR validation identified novel enzymes in the primary metabolism of staphylococci. Gene expression response analysis and metabolic modeling demonstrated the adaptation of enzymes to IQ-143, including those not affected by significant gene expression changes. At lower concentrations, IQ-143 was bacteriostatic, and at higher concentrations bactericidal, while the analysis suggested that the mode of action was a direct interference in nucleotide and energy metabolism. Experiments in human cell lines supported the conclusions from pathway modeling and found that IQ-143 had low cytotoxicity. Conclusions: The data suggest that IQ-143 is a promising lead compound for antibiotic therapy against staphylococci. The combination of gene expression and metabolite analyses with in silico modeling of metabolite pathways allowed us to study metabolic adaptations in detail and can be used for the evaluation of metabolic effects of other xenobiotics

Optical Control of Cardiac Function with a Photoswitchable Muscarinic Agonist

Light-triggered reversible modulation of physiological functions offers the promise of enabling on-demand spatiotemporally controlled therapeutic interventions. Optogenetics has been successfully implemented in the heart, but significant barriers to its use in the clinic remain, such as the need for genetic transfection. Herein, we present a method to modulate cardiac function with light through a photoswitchable compound and without genetic manipulation. The molecule, named PAI, was designed by introduction of a photoswitch into the molecular structure of an M2 mAChR agonist. In vitro assays revealed that PAI enables light-dependent activation of M2 mAChRs. To validate the method, we show that PAI photoisomers display different cardiac effects in a mammalian animal model, and demonstrate reversible, real-time photocontrol of cardiac function in translucent wildtype tadpoles. PAI can also effectively activate M2 receptors using two-photon excitation with near-infrared light, which overcomes the scattering and low penetration of short-wave-length illumination, and offers new opportunities for intravital imaging and control of cardiac function