Epiisopilosine alkaloid has activity against Schistosoma mansoni in mice without acute toxicity.

Schistosomiasis is a disease caused by parasites of the genus Schistosoma, currently affecting more than 200 million people. Among the various species of this parasite that infect humans, S. mansoni is the most common. Pharmacological treatment is limited to the use of a single drug, praziquantel (PZQ), despite reports of parasite resistance and low efficacy. It is therefore necessary to investigate new potential schistosomicidal compounds. In this study, we tested the efficacy of epiisopilosine (EPIIS) in a murine model of schistosomiasis. A single dose of EPIIS (100 or 400 mg/kg) administered orally to mice infected with adult S. mansoni resulted in reduced worm burden and egg production. The treatment with the lower dose of EPIIS (100 mg/kg) significantly reduced total worm burden by 60.61% (P < 0.001), as well as decreasing hepatosplenomegaly and egg excretion. Scanning electron microscopy revealed morphological changes in the worm tegument after treatment. Despite good activity of EPIIS in adult S. mansoni, oral treatment with single dose of EPIIS 100 mg/kg had only moderate effects in mice infected with juvenile S. mansoni. In addition, we performed cytotoxicity and toxicological studies with EPIIS and found no in vitro cytotoxicity (in HaCaT, and NIH-3T3 cells) at a concentration of 512 µg/mL. We also performed in silico analysis of toxicological properties and showed that EPIIS had low predicted toxicity. To confirm this, we investigated systemic acute toxicity in vivo by orally administering a 2000 mg/kg dose to Swiss mice. Treated mice showed no significant changes in hematological, biochemical, or histological parameters compared to non-treated animals. Epiisopilosine showed potential as a schistosomicidal drug: it did not cause acute toxicity and it displayed an acceptable safety profile in the animal model.

Antiparasitic, structural, pharmacokinetic, and toxicological properties of riparin derivatives.

Schistosomiasis, caused by helminth flatworms of the genus Schistosoma, is one of the most important parasitic diseases in the world, affecting over 200 million people in developing countries. Riparins are natural alkamides found in Aniba riparia (Lauraceae) fruits that possess several pharmacological properties. In this study, we reported the synthesis, characterization and structural analysis of six riparin derivatives (A-F), as well as their schistosomicidal activity against S. mansoni worms together with a biological, pharmacokinetic and toxicological in silico evaluation. Firstly, these compounds were synthesized, purified and characterized by elemental analysis, FT-IR spectroscopy, X-ray diffraction and theoretical calculations to evaluate their stability and conformation. Next, the schistosomicidal activity of the riparins was tested against S. mansoni worms. Bioassays revealed that Riparins E and F were the most active compounds, showing half-maximum inhibitory concentration at low micromolar ranges (IC50 values ~10 µM). Also, confocal laser scanning microscopy studies revealed tegumental damage in parasites after exposition with Riparins B, E and F. Additionally, based on MTT assay, all tested riparins showed no cytotoxic potential toward mammalian cells. Finally, in silico analyses were used to predict the absorption, distribution, metabolism, elimination and toxicity (ADMET) of the compounds. Taken together, the results revealed a promising ADMET profile and suggested that riparins could be starting points for lead optimization programs for natural products with antischistosomal properties.

Bergenin from Peltophorum dubium: Isolation, Characterization, and Antioxidant Activities in Non-Biological Systems and Erythrocytes.

BACKGROUND: Bergenin, a compound derived from gallic acid, is a secondary metabolite of the plant Peltophorum dubium (Spreng.) Taub. OBJECTIVE: In this study, we aimed to characterize the ability of bergenin to eliminate the radicals in non-biological systems. METHODS: We evaluated bergenin's ability to protect erythrocytes from oxidative damage in a biological system. We have elucidated bergenin structure using nuclear magnetic resonance, X-ray diffraction, Fourier transform infrared spectroscopy, and differential scanning calorimetry. We then evaluated its antioxidant capacity in vitro against DPPH•, ABTS•+, hydroxyl radicals, and nitric oxide, and determined its ability to transfer electrons owing to its reduction potential and ability to chelate iron. We also evaluated its protective capacity against oxidative damage produced by AAPH in erythrocytes, its hemolytic properties, its ability to inhibit hemolysis, and its ability to maintain intracellular reduced glutathione homeostasis. RESULTS: Bergenin concentrations between 0.1 and 3mM significantly (p < 0.05) and dose dependently decreased formation of ABTS•+, DPPH•, nitrite ions, OH•, reduced formation ferricyanide, ferrozine-Fe2+complex, inhibited AAPH-induced oxidative hemolysis of erythrocytes, raised GSH levels in the presence of AAPH, inhibited AAPH-induced lipid peroxidation in erythrocytes. CONCLUSION: Bergenin may represent a novel alternative antioxidant, with potential applications in various industries, including drugs, cosmetics, and foods.

Discovery of Novel Antischistosomal Agents by Molecular Modeling Approaches.

Schistosomiasis, a chronic neglected tropical disease caused by Schistosoma worms, is reported in nearly 80 countries. Although the disease affects approximately 260 million people, the treatment relies exclusively on praziquantel, a drug discovered in the mid-1970s that lacks efficacy against the larval stages of the parasite. In addition, the dependence on a single treatment has raised concerns about drug resistance, and reduced susceptibility has already been found in laboratory and field isolates. Therefore, novel therapies for schistosomiasis are needed, and several approaches have been used to that end. One of these strategies, molecular modeling, has been increasingly integrated with experimental techniques, resulting in the discovery of novel antischistosomal agents.

Layer-by-layer films containing peptides of the Cry1Ab16 toxin from Bacillus thuringiensis for potential biotechnological applications.

Cry1Ab16 is a toxin of crystalline insecticidal proteins that has been widely used in genetically modified organisms (GMOs) to gain resistance to pests. For the first time, in this study, peptides derived from the immunogenic Cry1Ab16 toxin (from Bacillus thuringiensis) were immobilized as layer-by-layer (LbL) films. Given the concern about food and environmental safety, a peptide with immunogenic potential, PcL342-354C, was selected for characterization of the electrochemical, optical, and morphological properties. The results obtained by cyclic voltammetry (CV) showed that the peptide have an irreversible oxidation process in electrolyte of 0.1 mol · L(-1) potassium phosphate buffer (PBS) at pH7.2. It was also observed that the electrochemical response of the peptide is governed mainly by charge transfer. In an attempt to maximize the electrochemical signal of peptide, it was intercalated with natural (agar, alginate and chitosan) or synthetic polymers (polyethylenimine (PEI) and poly(sodium 4-styrenesulfonate (PSS)). The presence of synthetic polymers on the film increased the electrochemical signal of PcL342-354C up to 100 times. Images by Atomic Force Microscopy (AFM) showed that the immobilized PcL342-354C formed self-assembled nanofibers with diameters ranging from 100 to 200 nm on the polymeric film. By UV-Visible spectroscopy (UV-Vis) it was observed that the ITO/PEI/PSS/PcL342-354C film grows linearly up to the fifth layer, thereafter tending to saturation. X-ray diffraction confirmed the presence on the films of crystalline ITO and amorphous polypeptide phases. In general, the ITO/PEI/PSS/PcL342-354C film characterization proved that this system is an excellent candidate for applications in electrochemical sensors and other biotechnological applications for GMOs and environmental indicators.

Structural parameters, molecular properties, and biological evaluation of some terpenes targeting Schistosoma mansoni parasite.

The use of natural products has a long tradition in medicine, and they have proven to be an important source of lead compounds in the development of new drugs. Among the natural compounds, terpenoids present broad-spectrum activity against infective agents such as viruses, bacteria, fungi, protozoan and helminth parasites. In this study, we report a biological screening of 38 chemically characterized terpenes from different classes, which have a hydroxyl group connected by hydrophobic chain or an acceptor site, against the blood fluke Schistosoma mansoni, the parasite responsible for schistosomiasis mansoni. In vitro bioassays revealed that 3,7-dimethyl-1-octanol (dihydrocitronellol) (10) was the most active terpene (IC50 values of 13-52 µM) and, thus, we investigated its antischistosomal activity in greater detail. Confocal laser scanning microscopy revealed that compound 10 induced severe tegumental damage in adult schistosomes and a correlation between viability and tegumental changes was observed. Furthermore, we compared all the inactive compounds with dihydrocitronellol structurally by using shape and charge modeling. Lipophilicity (miLogP) and other molecular properties (e.g. molecular polar surface area, molecular electrostatic potential) were also calculated. From the 38 terpenes studied, compound 10 is the one with the greatest flexibility, with a sufficient apolar region by which it may interact in a hydrophobic active site. In conclusion, the integration of biological and chemical analysis indicates the potential of the terpene dihydrocitronellol as an antiparasitic agent.

Anthelmintic activity in vivo of epiisopiloturine against juvenile and adult worms of Schistosoma mansoni.

Schistosomiasis is a serious disease currently estimated to affect more that 207 million people worldwide. Due to the intensive use of praziquantel, there is increasing concern about the development of drug-resistant strains. Therefore, it is necessary to search for and investigate new potential schistosomicidal compounds. This work reports the in vivo effect of the alkaloid epiisopiloturine (EPI) against adults and juvenile worms of Schistosoma mansoni. EPI was first purified its thermal behavior and theoretical solubility parameters charaterised. In the experiment, mice were treated with EPI over the 21 days post-infection with the doses of 40 and 200 mg/kg, and 45 days post-infection with single doses of 40, 100 and 300 mg/kg. The treatment with EPI at 40 mg/kg was more effective in adult worms when compared with doses of 100 and 300 mg/kg. The treatment with 40 mg/kg in adult worms reduced parasite burden significantly, lead to reduction in hepatosplenomegaly, reduced the egg burden in faeces, and decreased granuloma diameter. Scanning electron microscopy revealed morphological changes to the parasite tegument after treatment, including the loss of important features. Additionally, the in vivo treatment against juvenile with 40 mg/kg showed a reduction of the total worm burden of 50.2%. Histopathological studies were performed on liver, spleen, lung, kidney and brain and EPI was shown to have a DL50 of 8000 mg/kg. Therefore EPI shows potential to be used in schistosomiasis treatment. This is the first time that schistosomicidal in vivo activity of EPI has been reported.

Collagen-based silver nanoparticles for biological applications: synthesis and characterization.

BACKGROUND: Type I collagen is an abundant natural polymer with several applications in medicine as matrix to regenerate tissues. Silver nanoparticles is an important nanotechnology material with many utilities in some areas such as medicine, biology and chemistry. The present study focused on the synthesis of silver nanoparticles (AgNPs) stabilized with type I collagen (AgNPcol) to build a nanomaterial with biological utility. Three formulations of AgNPcol were physicochemical characterized, antibacterial activity in vitro and cell viability assays were analyzed. AgNPcol was characterized by means of the following: ultraviolet-visible spectroscopy, dynamic light scattering analysis, Fourier transform infrared spectroscopy, atomic absorption analysis, transmission electron microscopy and of X-ray diffraction analysis. RESULTS: All AgNPcol showed spherical and positive zeta potential. The AgNPcol at a molar ratio of 1:6 showed better characteristics, smaller hydrodynamic diameter (64.34 ± 16.05) and polydispersity index (0.40 ± 0.05), and higher absorbance and silver reduction efficiency (0.645 mM), when compared with the particles prepared in other mixing ratios. Furthermore, these particles showed antimicrobial activity against both Staphylococcus aureus and Escherichia coli and no toxicity to the cells at the examined concentrations. CONCLUSIONS: The resulted particles exhibited favorable characteristics, including the spherical shape, diameter between 64.34 nm and 81.76 nm, positive zeta potential, antibacterial activity, and non-toxicity to the tested cells (OSCC).

4-{5-[(2-Bromo-benz-yl)sulfan-yl]-1H-tetra-zol-1-yl}benzoic acid.

In the title compound, C15H11BrN4O2S, the tetra-zole ring makes dihedral angles of 45.97 (10) and 75.41 (1)°, respectively, with the benzoyl and bromo-benzene rings while the dihedral angle between the benzene rings is 73.77 (1)°. In the crystal, mol-ecules are linked through O-H⋯ N and C-H⋯ O hydrogen bonds, giving infinite chains in both the [110] and [1-10] directions. These chains are further connected by C-Br⋯π and C-O⋯π inter-actions and also by π-π stacking between tetra-zole rings [centroid-centroid distance = 3.312 (1) Å], generating a three-dimensional network.

2-({1-[2-(Methyl-sulfan-yl)phen-yl]-1H-tetra-zol-5-yl}sulfan-yl)acetic acid.

In the title compound, C10H10N4O2S2, the tetra-zole and benzene rings are almost normal to one another, with a dihedral angle between their planes of 84.33 (9)°. In the crystal, mol-ecules are linked via pairs of bifurcated O-H⋯(N,N) hydrogen bonds, forming inversion dimers with graph-set motif R 4 (4)(12). The dimers are linked by significant π-π inter-actions involving inversion-related tetra-zole rings and inversion-related benzene rings, with centroid-centroid distances of 3.7376 (14) and 3.8444 (15) Å, respectively.

µ-Azido-κ(2) N (1):N (1)-µ-chlorido-bis-[(2-chloro-3-dimethyl-amino-1-phenyl-prop-1-en-1-yl-κ(2) C (1),N)palladium(II)] chloro-form monosolvate.

In the binuclear title complex, [Pd2(C11H13ClN)2Cl(N3)]·CHCl3, each Pd(II) atom has a slightly distorted square-planar geometry being coordinated by a C and an N atom of the 2-chloro-3-dimethyl-amino-1-phenyl-propyl ligand, a bridging Cl atom and an N atom of a bridging end-on azide group. There is a short intra-molecular C-H⋯Cl contact in the complex mol-ecule. In the crystal, the chloro-form solvent mol-ecule is linked to the complex via a C-H⋯π inter-action.

(Benzyl isocyanide-κC (1))chlorido(2-chloro-3-dimethyl-amino-1-phenyl-prop-1-en-1-yl-κ(2) C (1),N)palladium(II).

In the title compound, [Pd(C11H13ClN)Cl(C8H7N)], which crystallized in the chiral space group P212121, the Pd(II) atom is coordinated by two C atoms, a Csp(2) atom of the 2-chloro-3-dimethyl-amino-1-phenyl-prop-1-en-1-yl ligand and a Csp atom from the benzyl isocyanide ligand, as well as an N atom of the ligand and a Cl atom, in a square-planar geometry. In the complex, there is a short C-H⋯Cl hydrogen bond and a C-H⋯π inter-action. In the crystal, mol-ecules are linked via C-H⋯Cl hydrogen bonds, forming chains along the a-axis direction.

Potassium morpholine-4-carbodithio-ate monohydrate.

In the ionic title compound, K(+)·C(5)H(8)NOS(2) (-)·H(2)O, the morpholine ring of the morpholine-4-carbodithio-ate anion has a chair conformation. The potassium cation is coordinated by four S and four O atoms in a bipyramidal reversed geometry. In the crystal, the three components are linked, generating infinite two-dimensional networks that lie parallel to the bc plane. These layers are linked via O-H⋯S hydrogen bonds, forming a three-dimensional structure.

Morpholin-4-ium morpholine-4-carbo-dithio-ate.

The title compound, C(4)H(10)NO(+)·C(5)H(8)NOS(2) (-), is built up of a morpholinium cation and a dithio-carbamate anion. In the crystal, two structurally independent formula units are linked via N-H⋯S hydrogen bonds, forming an inversion dimer, with graph-set motif R(4) (4)(12).

Sodium piperidine-1-carbodithio-ate dihydrate.

The asymmetric unit of the title compound, Na(+)·C(6)H(10)NS(2) (-)·2H(2)O, is composed of a sodium cation, a piperidine-dithio-carbamate anion which exhibits positional disorder, and two lattice water mol-ecules. The atoms of the piperidine ring are divided over two sites with occupancy factors of 0.554 (6) and 0.446 (6). In the crystal, the sodium cation (coordination number of 6) and the piperidine-dithio-carbamate anion are linked, forming an infinite two-dimensional network extending parallel to (001). O-H⋯S hydrogen bonds, involving the lattice water mol-ecules, also aid in stabilizing the crystal sructure.

Ammonium piperidine-1-carbodithio-ate.

The title compound, NH(4) (+)·C(6)H(10)NS(2) (-), is composed of an ammonium cation and a piperidine-1-carbodithio-ate anion which exhibits positional disorder. The atoms of the ring have a structural disorder and they are divided into two sites, with occupancy factors of 0.584 and 0.426.. In the crystal, the cation and anion are linked by N-H⋯S hydrogen bonds to form an infinite two-dimensional network.