Structures and biological activity of three 2-(pyridin-2-yl)-1H-benzimidazole derivatives.

Two new 2-(pyridin-2-yl)-1H-benzimidazole derivatives, namely, 2-(4-phenoxypyridin-2-yl)-1H-benzimidazole, C18H13N3O, and 2-[4-(4-fluorophenoxy)pyridin-2-yl]-1H-benzimidazole, C18H12FN3O, were synthesized and characterized by NMR spectroscopy. Crystal structure, biological activity and ADME analyses were performed for these two new compounds and a third compound, namely, 5,6-dimethyl-2-[4-(4-phenylpiperazin-1-yl)pyridin-2-yl]-1H-benzimidazole methanol monosolvate, C24H25N5·CH3OH, the synthesis of which had been described previously. All three compounds have a similar chain hydrogen-bonding pattern. One of them (the fluorophenoxy derivative) showed good antimicrobial activity against Gram-positive bacteria. The ADME analysis indicates that the compounds could be good drug candidates.

Synthesis and Biological Activity of Piperidinothiosemicarbazones Derived from Aminoazinecarbonitriles.

To investigate how structural modifications affect tuberculostatic potency, we synthesized seven new piperidinothiosemicrabazone derivatives 8-14, in which three of them had a pyrazine ring replacing the pyridine ring. Derivatives 8-9 and 13-14 exhibited significant activity against the standard strain (minimum inhibitory concentration (MIC) 2-4 µg/mL) and even greater activity against the resistant M. tuberculosis strain (MIC 0.5-4 µg/mL). Additionally, the effects of compounds 8-9 were entirely selective (MIC toward other microorganisms ≥ 1000 µg/mL) and non-toxic (IC50 to HaCaT cells 5.8 to >50 µg/mL). The antimycobacterial activity of pyrazine derivatives 11-12 was negligible (MIC 256 to >500 µg/mL), indicating that replacing the aromatic ring was generally not a promising line of research in this case. The zwitterionic structure of compound 11 was determined using X-ray crystallography. Absorption, distribution, metabolism, and excretion (ADME) calculations showed that all compounds, except 11, could be considered for testing as future drugs. An analysis of the structure-activity relationship was carried out, indicating that the higher basicity of the substituent located at the heteroaromatic ring might be of particular importance for the antituberculous activity of the tested groups of compounds.

LC-MS/MS Evaluation of Pyrrolizidine Alkaloids Profile in Relation to Safety of Comfrey Roots and Leaves from Polish Sources.

Comfrey (Symphytum officinale L.) has a long tradition of use in the treatment of musculoskeletal disorders. However, due to hepatotoxic pyrrolizidine alkaloids (PAs), the EMA restricts the use of comfrey root (CR) to external use only and for short periods of time. Recent studies indicate a low permeability of PAs across the skin, calling into question the safety of topical application of products containing comfrey preparations. The aim of our work was to develop and validate an HPLC method enabling the separation of isomeric PAs from comfrey and, on this basis, to assess the potential toxicity of CR and comfrey leaf (CL) obtained from various Polish sources. The qualitative and quantitative analysis of PAs via HPLC-MS/MS was performed in MRM mode. The results obtained confirmed a lower content of PAs in CL than in CR and showed a wide variation in the composition of PAs in CR, with a much more stable profile of PAs in CL. Factor analysis confirmed that CRs and CLs differ in PA content, which is influenced by the growth conditions and geographical origin. The determined concentrations of PAs prove that in some CRs available on the Polish herbal market, the content of PAs may exceed the daily dose considered safe.

Synthesis, structure, ADME and biological activity of three 2,6-disubstituted thiosemicarbazone derivatives.

Three new 2,6-disubstituted thiosemicarbazone derivatives of pyridine, namely, 2-{amino[6-(pyrrolidin-1-yl)pyridin-2-yl]methylidene}-N,N-dimethylhydrazine-1-carbothioamide, C13H20N6S, 2-{amino[6-(piperidin-1-yl)pyridin-2-yl]methylidene}-N,N-dimethylhydrazine-1-carbothioamide, C14H22N6S, and 2-[amino(6-phenoxypyridin-2-yl)methylidene]-N,N-dimethylhydrazine-1-carbothioamide monohydrate, C15H17N5OS·H2O, have been synthesized and characterized by NMR spectroscopy and low-temperature single-crystal X-ray diffraction. In addition, their antibacterial and anti-yeast activities have been determined. The ability of the tested compounds to inhibit bacterial growth was comparable to vancomycin as a reference drug. Compared to isoniazid (MIC 0.125 and 8 µg ml-1), the compounds showed the ability to inhibit the growth of Mycobacterium tuberculosis to a moderate degree for the standard strain and at the same level or higher (MIC 4-8 µg ml-1) for the resistant strain. All three compounds adopt the zwitterionic form in the crystal structure regardless of the presence or absence of solvent molecules.

Structure and Microbiological Activity of 1H-benzo[d]imidazole Derivatives.

Three new crystal structures of 1H-benzo[d]imidazole derivatives were determined. In the structures of these compounds, an identical system of hydrogen bonds, C(4), was observed. Solid-state NMR was applied for testing the quality of the obtained samples. All of these compounds were tested for in vitro antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, as well as antifungal activity, by checking their selectivity. ADME calculations indicate that the compounds can be tested as potential drugs.

Synthesis and Structure-Activity Relationship of 2,6-Disubstituted Thiosemicarbazone Derivatives of Pyridine as Potential Antituberculosis Agents.

In this study, six new 2,6-disubstituted thiosemicarbazone derivatives of pyridine were synthesized (4−9), and their tuberculostatic activity was evaluated. All of them showed two- to eightfold higher activity (minimum inhibitory concentration (MIC) 0.5−4 µg/mL) against the resistant strain compared with the reference drug. Compounds 5 and 7, which contained the most basic substituents­pyrrolidine and piperidine­in their structure, strongly inhibited the growth of the standard strain (MIC 2 µg/mL). Furthermore, the same derivatives exhibited activity comparable to that of the reference drugs against some types of Gram-positive bacteria (MIC 0.49 µg/mL) and showed no cytotoxicity (IC50 > 50 µg/mL) in HaCaT cells. The zwitterionic structure of each compound was determined using X-ray crystallography. Absorption, distribution, metabolism, and excretion analyses showed that all compounds are good drug candidates. Thus, compounds 5 and 7 were identified as leading structures for further research on antituberculosis drugs with extended effects.

Anticancer and antimicrobial activity of new copper (II) complexes.

In this study, three new organic ligands N'-(benzylidene)-6-chloropyrazine-2-carbohydrazonamide (L1), 6-chloro-N'-(4-nitrobenzylidene)picolinohydrazonamide(L2), and N'-(benzylidene)-4-chloropicolinohydrazonamide (L3) and three copper coordination compounds (Cu(L1)Cl2, Cu(L2)Cl2 and Cu(L3)Cl2) based on them were synthesized. All obtained compounds were characterized using appropriate analytical techniques: elemental analysis (EA), thermogravimetric analysis (TG-DTG), Fourier transform infrared spectroscopy (FTIR) and flame-atomic absorption spectrometry (F-AAS). These methods of physicochemical analyses helped to assume that the complexation in three cases proceeds in a bidentate manner. The X-ray investigation confirmed the synthesis pathway and molecular structures for L1 and L3 ligands. The antimicrobial activity of the obtained compounds was then comprehensively investigated, where Cu(L3)Cl2 showed the strongest antibacterial properties against all tested bacteria (Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli). LN229 human glioma cells and BJ human normal fibroblasts cells were treated with tested compounds and their cytotoxicity was evaluated with MTT test. The effect of complexing on antitumor activity has been investigated. The ligand L1 and its complex showed similar activity against normal cells while complexation increases toxicity against cancer cells in concentrations of 50 and 100 µM. For the one pair of ligand/complex compounds the apoptosis detection, cell cycle analysis and gene expression analysis (qRT-PCR) were performed. Cu(L1)Cl2 showed the stronger toxic effect in comparison with L1 due to the population of early apoptotic cells which revealed metabolic activity in MTT assay.

Synthesis and new skin-relevant properties of the salicylic acid ester of bakuchiol.

Bakusylan (bakuchiol salicylate) is a bipartite compound obtained by merging two skin-active entities with complementary bioactivities-bakuchiol and salicylic acid-for the purpose of generating a new class of functional retinoids with enhanced skin benefits. Here, we describe its preparation process and report that pure bakusylan exhibits potential for an improved permeation through the stratum corneum, enhances type IV collagen gene expression in organotypic skin substitutes containing both epidermal and dermal layers, and upregulates this protein in adult human dermal fibroblast cultures. The mechanism of action underlying these effects appears to involve the components of the IP3K/Akt signaling pathway selectively implicated in the maintenance of skin integrity, further underlying the suitability of this ester for skin care applications requiring enhanced cutaneous permeation targeting the dermal-epidermal junction.

In Silico ADME and Toxicity Prediction of Benzimidazole Derivatives and Its Cobalt Coordination Compounds. Synthesis, Characterization and Crystal Structure.

As a result of the synthesis, three new solids, cobalt (II) coordination compounds with benzimidazole derivatives, and chlorides were obtained. The ligands that were used in the synthesis were specially synthesized and were commercially unavailable. During the synthesis, a single crystal of the complex with the L1 ligand was obtained and the crystal structure was refined. All coordination compounds were characterized by elemental analysis, infrared spectroscopy, and thermogravimetric analysis. All the obtained data allowed one to determine the formulas of the new compounds, as well as to determine the method of metal-ligand coordination. Thermal analysis allowed to know the temperature stability of the compounds, solids intermediate and final products of pyrolysis. Additionally, volatile decomposition and fragmentation products have been identified. The toxicity of the compounds and their bioavailability were determined using in silico methods. By predicting activity on cell lines, the potential use of compounds as chemotherapeutic agents has been specified. The blood-brain barrier crossing and the gastrointestinal absorption were defined. Pharmaceutical biodistribution was also simulated.

N'-Substituted 4-Phenylpicolinohydrazonamides with Thiosemicarbazone Moiety as New Potential Antitubercular Agents: Synthesis, Structure and Evaluation of Antimicrobial Activity.

Three new 4-phenylpicolin derivatives with a thiosemicarbazone structure were synthesized and evaluated for tuberculostatic activity. The compounds were obtained by the condensation of methyl 4-phenylpicolonimidate with the corresponding cycloalkylamino-1-carbothiohydrazides. The 1H NMR temperature spectra obtained showed proton lability at the nitrogen atom N2, and X-ray crystallography confirmed the zwitterionic structure of all products. ADME calculations indicate that the compounds can be tested as future drugs. All compounds were absorbed in the gastrointestinal tract. All compounds also showed very good tuberculostatic activity (MIC 3.1-12.5 µg/mL). Derivative 1b showed the best selectivity for M. tuberculosis compared to the other pathogenic species tested. The study has allowed the emergence of imine derivative 1b as a good structure for further optimization in the search for antitubercular drugs.

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.

New Coordination Compounds Based on a Pyrazine Derivative: Design, Characterization, and Biological Study.

New coordination compounds of Mn(II), Fe(III), Co(II), and Ni(II) and the biologically active ligand L (N'-benzylidenepyrazine-2-carbohydrazonamide) were synthesized and characterized by appropriate analytical techniques: elemental analysis (EA), thermogravimetric analysis (TG-DTG), infrared spectroscopy (FTIR), and flame-atomic absorption spectrometry (F-AAS). The biological activity of the obtained compounds was then comprehensively investigated. Rational use of these compounds as potential drugs was proven by ADME analysis. All obtained compounds were screened in vitro for antibacterial, antifungal, and anticancer activities. Some of the studied complexes exhibited significantly higher activity than the ligand alone.

Zinc Coordination Compounds with Benzimidazole Derivatives: Synthesis, Structure, Antimicrobial Activity and Potential Anticancer Application.

Developing new, smart drugs with the anticancer activity is crucial, especially for cancers, which cause the highest mortality in humans. In this paper we describe a series of coordination compounds with the element of health, zinc, and bioactive ligands, benzimidazole derivatives. By way of synthesis we have obtained four compounds named C1, C2, C4 and C4. Analytical analyses (elemental analysis (EA), flame atomic absorption spectrometry (FAAS)), spectroscopic (Fourier transform infrared spectroscopy (FT-IR), mass spectrometry (MS)) and thermogravimetric (TG) methods and the definition of crystal structures were used to explore the nature of bonding and to elucidate the chemical structures. The collected analytical data allowed the determination of the stoichiometry in coordination compounds, thermal stability, crystal structure and way of bonding. The cytotoxicity effect of the new compounds as a potential antitumor agent on the glioblastoma (T98G), neuroblastoma (SK-N-AS) and lung adenocarcinoma (A549) cell lines and human normal skin fibroblasts (CCD-1059Sk) was also determined. Cell viability was determined by the MTT assay. The results obtained confirmed that conversion of ligands into the respective metal complexes significantly improved their anticancer properties. The complexes were screened for antibacterial and antifungal activities. The ADME technique was used to determine the physicochemical and biological properties.

Differences in the Structure and Antimicrobial Activity of Hydrazones Derived from Methyl 4-Phenylpicolinimidate.

Four novel methyl 4-phenylpicolinoimidate derivatives of hydrazone have been synthesized and evaluated for their antimicrobial activity, including tuberculostatic activity. The compounds obtained are condensates of hydrazonamide or hydrazide with 5-nitro-2-furaldehyde or 5-nitro-2-thiophenecarboxaldehyde. The antimicrobial activity of the tested compounds varied. Compound 3b exhibited significant activity against the tested Gram-positive bacteria (7.8-250 µg/mL). The results of structural tests revealed that the compound is the only one obtained in the form of a Z isomer. Tuberculostatic activity tests showed higher activity of derivatives 3a and 4a containing nitrofuran systems (MICs 3.1-12.5 µg/mL). This research allowed us to identify hydrazone 3b as a starting point for further optimization in the search for antimicrobial drugs. Likewise, compound 4a appears to be a good guiding structure for use in future research on new anti-tuberculosis drugs.

Antitumor Activity against A549 Cancer Cells of Three Novel Complexes Supported by Coating with Silver Nanoparticles.

A novel biologically active organic ligand L (N'-benzylidenepyrazine-2-carbohydrazonamide) and its three coordination compounds have been synthesized and structurally described. Their physicochemical and biological properties have been thoroughly studied. Cu(II), Zn(II), and Cd(II) complexes have been analyzed by F-AAS spectrometry and elemental analysis. The way of metal-ligand coordination was discussed based on FTIR spectroscopy and UV-VIS-NIR spectrophotometry. The thermal behavior of investigated compounds was studied in the temperature range 25-800 °C. All compounds are stable at room temperature. The complexes decompose in several stages. Magnetic studies revealed strong antiferromagnetic interaction. Their cytotoxic activity against A549 lung cancer cells have been studied with promising results. We have also investigated the biological effect of coating studied complexes with silver nanoparticles. The morphology of the surface was studied using SEM imaging.

Relationship between the Crystal Structure and Tuberculostatic Activity of Some 2-Amidinothiosemicarbazone Derivatives of Pyridine.

Tuberculosis remains one of the most common diseases affecting developing countries due to difficult living conditions, the rapidly increasing resistance of M. tuberculosis strains and the small number of effective anti-tuberculosis drugs. This study concerns the relationship between molecular structure observed in a solid-state by X-ray diffraction and the 15N NMR of a group of pyridine derivatives, from which promising activity against M. tuberculosis was reported earlier. It was found that the compounds exist in two tautomeric forms: neutral and zwitterionic. The latter form forced the molecules to adopt a stable, unique, flat frame due to conjugation and the intramolecular hydrogen bond system. As the compounds exist in a zwitterionic form in the crystal state generally showing higher activity against tuberculosis, it may indicate that this geometry of molecules is the "active" form.

Characterization of Metal-Bound Benzimidazole Derivatives, Effects on Tumor Cells of Lung Cancer.

Four new ligands and four new copper (II) coordination compounds were prepared and characterized by chemical, elemental analysis, cytotoxicity, and FTIR spectroscopy (Fourier transform infrared spectroscopy). The nature of metal-ligand coordination was investigated. The thermal properties of complexes in the solid state were studied using TG-MS techniques (thermogravimetric analysis coupled with mass spectrometry) under dynamic flowing air atmosphere to analyze the principal volatile thermal decomposition and fragmentation products that evolved during thermolysis. The intermediate and final solid thermolysis products were also determined. The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) assay was used to evaluate active metabolic cells as an IC50 (half maximal inhibitory concentration). The relationship between antitumor activity and the position of nitrogen atoms in the organic ligand has been shown.

Synthesis, structure and biological activity of four new picolinohydrazonamide derivatives.

Four new picolinohydrazonamide derivatives, namely, 6-methyl-N'-(morpholine-4-carbonothioyl)picolinohydrazonamide, C12H17N5OS, 6-chloro-N'-(morpholine-4-carbonothioyl)picolinohydrazonamide methanol monosolvate, C11H14ClN5OS·CH3OH, 6-chloro-N'-(4-phenylpiperazine-1-carbonothioyl)picolinohydrazonamide, C17H19ClN6S, and 6-chloropicolinohydrazonamide, C6H7ClN4, have been synthesized and characterized by NMR spectroscopy and single-crystal low-temperature X-ray diffraction. In addition, their antibacterial and anti-yeast activities have been determined. The first three compounds adopt the zwitterionic form in the crystal structure regardless of the presence or absence of solvent molecules in the structure. They also adopt the same symmetry, i.e. P21/c (P21/n), unlike the fourth structure which is chiral and has the space group P212121. For all the studied cases, intermolecular N-H...O and N-H...N hydrogen bonds play an essential role in the formation of the structures.

4-Substituted picolinohydrazonamides as a new class of potential antitubercular agents.

The series of new 4-substituted picolinohydrazonamides were synthesized (6-25) and evaluated for tuberculostatic activity. Compounds having a hydrophilic cyclic amine such as morpholine and pyrrolidine at the end of the thiosemicarbazide chain, exhibited the highest antimycobacterial activity. The antimycobacterial activity of compounds 6, 11, and 15 (MIC 0.4-0.8 µg/mL) was higher than that of reference drugs. Moreover, derivative 15 exhibited lower activity against other tested microorganism such as bacteria gram-positive, gram-negative or fungi. Thus, this compound is characterized by the selectivity of antimicrobial activity. Antiproliferative study conducted against human dermal fibroblasts (HDF) and mouse melanoma cell line (B16-F10) revealed low cytotoxicity of compound 15. Conducted research allowed to identify compound 15 as leading for further research.

Active Benzimidazole Derivatives Targeting the MmpL3 Transporter in Mycobacterium abscessus.

The prevalence of pulmonary infections due to nontuberculous mycobacteria such as Mycobacterium abscessus has been increasing and surpassing tuberculosis (TB) in some industrialized countries. Because of intrinsic resistance to most antibiotics that drastically limits conventional chemotherapeutic treatment options, new anti-M. abscessus therapeutics are urgently needed against this emerging pathogen. Extensive screening of a library of benzimidazole derivatives that were previously shown to be active against Mycobacterium tuberculosis led to the identification of a lead compound exhibiting very potent in vitro activity against a wide panel of M. abscessus clinical strains. Designated EJMCh-6, this compound, a 2-(2-cyclohexylethyl)-5,6-dimethyl-1H-benzo[d]imidazole), also exerted very strong activity against intramacrophage-residing M. abscessus. Moreover, the treatment of infected zebrafish embryos with EJMCh-6 was correlated with significantly increased embryo survival and a decrease in the bacterial burden as compared to those for untreated fish. Insights into the mechanism of action were inferred from the generation of spontaneous benzimidazole-resistant strains and the identification of a large set of missense mutations in MmpL3, the mycolic acid transporter in mycobacteria. Overexpression of the mutated mmpL3 alleles in a susceptible M. abscessus strain was associated with high resistance levels to EJMCh-6 and to other known MmpL3 inhibitors. Mapping the mutations conferring resistance on an MmpL3 three-dimensional homology model defined a potential EJMCh-6-binding cavity. These data emphasize a yet unexploited chemical structure class against M. abscessus with promising translational development for the treatment of M. abscessus lung diseases.