Determination of the Primary Molecular Target of 1,2,4-Triazole-Ciprofloxacin Hybrids

We have synthesized and examined the antibacterial activity, toxicity and affinity towards bacterial type II topoisomerases of a series of 1,2,4-triazole-ciprofloxacin hybrids. A number of these compounds displayed enhanced activity against Gram-positive and Gram-negative bacteria when compared to ciprofloxacin. The toxic concentrations of the obtained derivatives, evaluated on HEK-293 cells using MTT assay, were much higher than concentrations required to produce antibacterial effect. Finally, the results of enzymatic studies showed that the analyzed compounds demonstrated other preferences as regards primary and secondary molecular targets than ciprofloxacin.This research was supported by the Ministry of Science and Higher Education under Iuventus Plus grant No. IP2014 037473. Tomasz Plech is a recipient of the Fellowship for Young Researchers with Outstanding Scientific Achievements from the Medical University of Lublin (Lublin, Poland)

Dawsonite as an indicator of multistage deformation and fluid pathways within fault zones: Insights from the Fore-Dukla Thrust Sheet, Outer Carpathians, Poland

The structural pattern developed within metre to microscopic scale thrust and strike-slip fault zones exposed in the Palaeogene flysch rocks of the Fore-Dukla Thrust Sheet in the south-eastern part of the Silesian Nappe, Outer Carpathians, Poland, reveals evidence for upper crustal deformation and fluid flow. Syntectonic dawsonite [NaAlCO3(OH)2] indicates the following series of deformational events within the fault zones: i) detachment and buckle folding resulting from movement along thrust faults; ii) faulting as a compensation of the shortening, resulting in the fault propagation folding, breakthrough thrust faulting and imbrications; and iii) strike-slip faulting. The microstructural pattern coupled with the growth of a related sequence of carbonate minerals within the fault zones, followed by present-day dawsonite precipitation and tufa formation, indicate a continuing influence of fluids within the Silesian Nappe up to and including modern time. Structural observations at metre to microscopic scales coupled with EDS mapping of rocks indicate that dawsonite is a unique tool for the reconstruction of subsequent deformation in the Fore-Dukla Thrust Sheet

Identification of the first-in-class dual inhibitors of human DNA topoisomerase IIα and indoleamine-2,3-dioxygenase 1 (IDO 1) with strong anticancer properties

Molecular docking of a large set of thiosemicarbazide-based ligands resulted in obtaining compounds that inhibited both human DNA topoisomerase IIα and indoleamine-2,3-dioxygenase-1 (IDO1). To the best of our knowledge, these compounds are the first dual inhibitors targeting these two enzymes. As both of them participate in the anticancer response, the effect of the compounds on a panel of cancer cell lines was examined. Among the cell lines tested, lung cancer (A549) and melanoma (A375) cells were the most sensitive to compounds 1 (IC50=0.23 µg/ml), 2 (IC50=0.83 µg/ml) and 3 (IC50=0.25 µg/ml). The observed activity was even 90-fold higher than that of etoposide, with selectivity index values reaching 125. In-silico simulations showed that contact between 1-3 and human DNA topoisomerase II was maintained through aromatic moieties located at limiting edges of ligand molecules and intensive interactions of the thiosemicarbazide core with the DNA fragments present in the catalytic site of the enzyme.</p

TZD-Based Hybrid Molecules Act as Dual Anti-Mycobacterium tuberculosis and Anti-Toxoplasma gondii Agents

Two distinct intracellular pathogens, namely Mycobacterium tuberculosis (Mtb) and Toxoplasma gondii (Tg), cause major public health problems worldwide. In addition, serious and challenging health problems of co-infections of Tg with Mtb have been recorded, especially in developing countries. Due to this fact, as well as the frequent cases of resistance to the current drugs, novel anti-infectious therapeutics, especially those with dual (anti-Tg and anti-Mtb) modes of action, are needed. To address this issue, we explored the anti-Tg potential of thiazolidinedione-based (TZD-based) hybrid molecules with proven anti-Mtb potency. Several TZD hybrids with pyridine-4-carbohydrazone (PCH) or thiosemicarbazone (TSC) structural scaffolds were more effective and more selective than sulfadiazine (SDZ) and trimethoprim (TRI). Furthermore, all of these molecules were more selective than pyrimethamine (PYR). Further studies for the most potent TZD-TSC hybrids 7, 8 and 10 and TZD-PCH hybrid molecule 2 proved that these compounds are non-cytotoxic, non-genotoxic and non-hemolytic. Moreover, they could cross the blood–brain barrier (BBB), which is a critical factor linked with ideal anti-Tg drug development. Finally, since a possible link between Tg infection and the risk of glioblastoma has recently been reported, the cytotoxic potential of TZD hybrids against human glioblastoma cells was also evaluated. TZD-PCH hybrid molecule 2 was found to be the most effective, with an IC50 of 19.36 ± 1.13 µg/mL against T98G cells

Determination of Some Isoquinoline Alkaloids in Extracts Obtained from Selected Plants of the Ranunculaceae, Papaveraceae and Fumarioideae Families by Liquid Chromatography and In Vitro and In Vivo Investigations of Their Cytotoxic Activity

Alkaloids are heterocyclic bases with widespread occurrence in nature. Plants are rich and easily accessible sources of them. Most isoquinoline alkaloids have cytotoxic activity for different types of cancer, including malignant melanoma, the most aggressive type of skin cancer. The morbidity of melanoma has increased worldwide every year. For that reason, developing new candidates for anti–melanoma drugs is highly needed. The aim of this study was to investigate the alkaloid compositions of plant extracts obtained from Macleaya cordata root, stem and leaves, Pseudofumaria lutea root and herb, Lamprocapnos spectabilis root and herb, Fumaria officinalis whole plant, Thalictrum foetidum root and herb, and Meconopsis cambrica root and herb by HPLC-DAD and LC-MS/MS. For determination of cytotoxic properties, human malignant melanoma cell line A375, human Caucasian malignant melanoma cell line G-361, and human malignant melanoma cell line SK-MEL-3 were exposed in vitro to the tested plant extracts. Based on the in vitro experiments, Lamprocapnos spectabilis herb extract was selected for further, in vivo research. The toxicity of the extract obtained from Lamprocapnos spectabilis herb was tested using an animal zebrafish model in the fish embryo toxicity test (FET) for determination of the LC50 value and non-toxic doses. Determination of the influence of the investigated extract on the number of cancer cells in a living organism was performed using a zebrafish xenograft model. Determination of the contents of selected alkaloids in different plant extracts was performed using high performance liquid chromatography (HPLC) in a reverse-phase system (RP) on a Polar RP column with a mobile phase containing acetonitrile, water and ionic liquid. The presence of these alkaloids in plant extracts was confirmed by LC-MS/MS. Preliminary cytotoxic activity of all prepared plant extracts and selected alkaloid standards was examined using human skin cancer cell lines A375, G-361, and SK-MEL-3. The cytotoxicity of the investigated extract was determined in vitro by cell viability assays (MTT). For in vivo determination of investigated extract cytotoxicity, a Danio rerio larvae xenograft model was used. All investigated plant extracts in in vitro experiments exhibited high cytotoxic activity against the tested cancer cell lines. The results obtained using the Danio rerio larvae xenograft model confirmed the anticancer activity of the extract obtained from Lamprocapnos spectabilis herb. The conducted research provides a basis for future investigations of these plant extracts for potential use in the treatment of malignant melanoma

Design, Synthesis, and Characterization of Novel Coordination Compounds of Benzimidazole Derivatives with Cadmium

Four complexes of Cd(II) with benzimidazole derivatives were synthesized and named C1, C2, C3, and C4. All coordination compounds were characterized through elemental analysis (EA), flame atomic absorption spectrometry (FAAS), Fourier-transform infrared spectroscopy (FTIR), thermogravimetric analysis coupled with mass spectrometry) (TG-MS), a cytotoxicity assay (MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide)), and computational chemical analysis for absorption, distribution, metabolism, and excretion (ADME). All of the obtained results are compatible and are consistent with the respective structures of the obtained compounds and their properties. The various techniques used allowed the determination of the composition, proposed structure of the compounds, their thermal stability and thermal properties, and the method of coordination between the metal (II) ion and the ligand. The ADME technique was also used to estimate the physicochemical and biological properties. The antitumor activity of the compounds was determined with an MTT assay on the glioblastoma (T98G), neuroblastoma (SK-N-AS), and lung adenocarcinoma (A549) cell lines, as well as normal human skin fibroblasts (CCD-1059Sk). Compound C2 was found to have potential antitumor properties and to be effective in inhibiting the growth of neuroblastoma cells. The antimicrobial activity of Cd complexes, free ligands, and reference drugs was tested against six strains of Gram-positive bacteria, five strains of Gram-negative rods, and three strains of yeasts. Compound C3 significantly increased activity against Gram-positive bacteria in comparison to the ligand

1,2,4-Triazole-based anticonvulsant agents with additional ROS scavenging activity are effective in a model of pharmacoresistant epilepsy

There are numerous studies supporting the contribution of oxidative stress to the pathogenesis of epilepsy. Prolonged oxidative stress is associated with the overexpression of ATP-binding cassette transporters, which results in antiepileptic drugs resistance. During our studies, three 1,2,4-triazole-3-thione derivatives were evaluated for the antioxidant activity and anticonvulsant effect in the 6 Hz model of pharmacoresistant epilepsy. The investigated compounds exhibited 2-3 times more potent anticonvulsant activity than valproic acid in 6 Hz test in mice, which is well-established preclinical model of pharmacoresistant epilepsy. The antioxidant/ROS scavenging activity was confirmed in both single-electron transfer-based methods (DPPH and CUPRAC) and during flow cytometric analysis of total ROS activity in U-87 MG cells. Based on the enzymatic studies on human carbonic anhydrases (CAs), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), one can assume that the herein investigated drug candidates will not impair the cognitive processes mediated by CAs and will have minimal off-target cholinergic effects

In Vitro and In Silico of Cholinesterases Inhibition and In Vitro and In Vivo Anti-Melanoma Activity Investigations of Extracts Obtained from Selected <i>Berberis</i> Species

Berberis species have a long history of use in traditional Chinese medicine, Ayurvedic medicine, and Western herbal medicine. The aim of this study was the quantification of the main isoquinoline alkaloids in extracts obtained from various Berberis species by HPLC, in vitro and in silico determination of anti-cholinesterase activity, and in vitro and in vivo investigations of the cytotoxic activity of the investigated plant extracts and alkaloid standards. In particular, Berberis species whose activity had not been previously investigated were selected for the study. In the most investigated Berberis extracts, a high content of berberine and palmatine was determined. Alkaloid standards and most of the investigated plant extracts exhibit significant anti-cholinesterase activity. Molecular docking results confirmed that both alkaloids are more favourable for forming complexes with acetylcholinesterase compared to butyrylcholinesterase. The kinetic results obtained by HPLC-DAD indicated that berberine noncompetitively inhibited acetylcholinesterase, while butyrylcholinesterase was inhibited in a mixed mode. In turn, palmatine exhibited a mixed inhibition of acetylcholinesterase. The cytotoxic activity of berberine and palmatine standards and plant extracts were investigated against the human melanoma cell line (A375). The highest cytotoxicity was determined for extract obtained from Berberis pruinosa cortex. The cytotoxic properties of the extract were also determined in the in vivo investigations using the Danio rerio larvae xenograft model. The obtained results confirmed a significant effect of the Berberis pruinosa cortex extract on the number of cancer cells in a living organism. Our results showed that extracts obtained from Berberis species, especially the Berberis pruinosa cortex extract, can be recommended for further in vivo experiments in order to confirm the possibility of their application in the treatment of neurodegenerative diseases and human melanoma