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Two new 2-(pyridin-2-yl)-1H-benzimidazole derivatives, namely, 2-(4-phenoxypyridin-2-yl)-1H-benzimidazole, C 18 H 13 N 3 O, and 2-[4-(4-fluorophenoxy)pyridin-2-yl]-1H-benzimidazole, C 18 H 12 FN 3 O, 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, C 24 H 25 N 5 ·CH 3 OH, 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.

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.

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.

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, C 13 H 20 N 6 S, 2-{amino[6-(piperidin-1-yl)pyridin-2-yl]methylidene}-N,N-dimethylhydrazine-1-carbothioamide, C 14 H 22 N 6 S, and 2-[amino(6-phenoxypyridin-2-yl)methylidene]-N,N-dimethylhydrazine-1-carbothioamide monohydrate, C 15 H 17 N 5 OS·H 2 O, 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.

In this study, three new organic ligands N'-(benzylidene)-6-chloropyrazine-2-carbohydrazonamide (L 1 ), 6-chloro-N'-(4-nitrobenzylidene)picolinohydrazonamide(L 2 ), and N'-(benzylidene)-4-chloropicolinohydrazonamide (L 3 ) and three copper coordination compounds (Cu(L 1 )Cl 2 , Cu(L 2 )Cl 2 and Cu(L 3 )Cl 2 ) 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 L 1 and L 3 ligands. The antimicrobial activity of the obtained compounds was then comprehensively investigated, where Cu(L 3 )Cl 2 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 L 1 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(L 1 )Cl 2 showed the stronger toxic effect in comparison with L 1 due to the population of early apoptotic cells which revealed metabolic activity in MTT assay., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

Three new crystal structures of 1 H -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.

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 substituents—pyrrolidine and piperidine—in 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.

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.

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 1 H 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.

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.

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.

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.

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.

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.

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 15 N 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.

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 IC 50 (half maximal inhibitory concentration). The relationship between antitumor activity and the position of nitrogen atoms in the organic ligand has been shown.

Four new picolinohydrazonamide derivatives, namely, 6-methyl-N'-(morpholine-4-carbonothioyl)picolinohydrazonamide, C 12 H 17 N 5 OS, 6-chloro-N'-(morpholine-4-carbonothioyl)picolinohydrazonamide methanol monosolvate, C 11 H 14 ClN 5 OS·CH 3 OH, 6-chloro-N'-(4-phenylpiperazine-1-carbonothioyl)picolinohydrazonamide, C 17 H 19 ClN 6 S, and 6-chloropicolinohydrazonamide, C 6 H 7 ClN 4 , 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. P2 1 /c (P2 1 /n), unlike the fourth structure which is chiral and has the space group P2 1 2 1 2 1 . 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.

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., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

1 H -benzo[ d ]imidazole derivatives exhibit antitubercular activity in vitro at a nanomolar range of concentrations and are not toxic to human cells, but their mode of action remains unknown. Here, we showed that these compounds are active against intracellular Mycobacterium tuberculosis To identify their target, we selected drug-resistant M. tuberculosis mutants and then used whole-genome sequencing to unravel mutations in the essential mmpL3 gene, which encodes the integral membrane protein that catalyzes the export of trehalose monomycolate, a precursor of the mycobacterial outer membrane component trehalose dimycolate (TDM), as well as mycolic acids bound to arabinogalactan. The drug-resistant phenotype was also observed in the parental strain overexpressing the mmpL3 alleles carrying the mutations identified in the resistors. However, no cross-resistance was observed between 1 H -benzo[ d ]imidazole derivatives and SQ109, another MmpL3 inhibitor, or other first-line antitubercular drugs. Metabolic labeling and quantitative thin-layer chromatography (TLC) analysis of radiolabeled lipids from M. tuberculosis cultures treated with the benzoimidazoles indicated an inhibition of trehalose dimycolate (TDM) synthesis, as well as reduced levels of mycolylated arabinogalactan, in agreement with the inhibition of MmpL3 activity. Overall, this study emphasizes the pronounced activity of 1 H -benzo[ d ]imidazole derivatives in interfering with mycolic acid metabolism and their potential for therapeutic application in the fight against tuberculosis., (Copyright © 2019 American Society for Microbiology.)

Tuberculosis still remains a very important problem, especially its multidrug resistant varieties (MDR-TB). Among the potential tuberculostatics, there are two benzimidazole derivatives, namely 5,6-dimethyl-2-phenylethylbenzo[d]imidazole (1) and (E)-5,6-dimethyl-2-styryl-1H-benzo[d]imidazole (2) which showed significant tuberculostatic activities, better than those of Pyrazinamide and Isoniazyd. Also, the cytotoxicity of 1 appeared promising. The compounds were studied (with the use of X-ray diffraction) in the form of the hemihydrate of 1, C 17 H 18 N 2 ·0.5H 2 O (1a), the methanol hemisolvate of 2, C 17 H 16 N 2 ·0.5CH 3 OH (2a), and the acid oxalate salt of 2, namely (E)-5,6-dimethyl-2-styryl-1H-benzo[d]imidazolium hydrogen oxalate, C 17 H 17 N 2 + ·C 2 HO 4 - (2b). All three structures reveal a similar extended conformation, despite the flexible linker between the two aromatic systems and the different types of strong intermolecular hydrogen bonds. The molecules of 2a are practically planar due to the double bond in the linker, which enables conjugation along the whole molecule, while the molecules of 1a exhibit the possibility of parallel orientations of their aromatic systems, despite the aliphatic (ethyl) linker.

Compounds possessing benzimidazole system exhibit significant antituberculous activity. In order to examine how structure modifications affect tuberculostatic activity, a series of benzazole derivatives were synthesized and screened for their antitubercular activity. The compounds 1 ⁻ 20 were obtained by the reaction between o -diamine, o -aminophenol, or o -aminothiophenol with carboxylic acids or thioamides. The newly synthesized compounds were characterized by IR, ¹H-NMR, 13 C-NMR spectra, and elemental analysis. Synthesized benzazoles were evaluated for their tuberculostatic activity toward Mycobacterium tuberculosis strains. Quantum chemical calculations were performed to study the molecular geometry and the electronic structure of benzimidazoles GK-151B, 4 , 6 , and benzoxazole 11 , using the Gaussian 03W software (Gaussian, Inc., Wallingford, CT, USA). Three-dimensional structure of benzimidazoles 1 ⁻ 3 , MC-9, and GK-151B was determined by ab initio calculation using Gamess-US software. The activity of the received benzimidazoles was moderate or good. All of the benzoxazoles and benzothiazoles demonstrated much lower activity. Benzoxazoles were less active by about 50 times, and benzothiazole by 100 times than the benzimidazole analogs. Quantum chemical calculations showed differences in the distribution of electrostatic potential in the benzazole system of benzimidazoles and benzoxazoles. Three-dimensional structure calculations revealed how the parity of the alkyl substituent at the C2 position impacts the activity. Benzimidazole system is essential for the antituberculosis activity that is associated with the presence of the imine nitrogen atom in N-1 position. Its replacement by an oxygen or sulfur atom results in a decrease of the activity. The parity of the alkyl substituent at the C-2 position also modifies the activity., Competing Interests: The authors declare no conflict of interest.

The search for new tuberculostatics is an important issue due to the increasing resistance of Mycobacterium tuberculosis to existing agents and the resulting spread of the pathogen. Heteroaryldithiocarbazic acid derivatives have shown potential tuberculostatic activity and investigations of the structural aspects of these compounds are thus of interest. Three new examples have been synthesized. The structure of methyl 2-[amino(pyridin-3-yl)methylidene]hydrazinecarbodithioate, C 8 H 10 N 4 S 2 , at 293 K has monoclinic (P2 1 /n) symmetry. It is of interest with respect to antibacterial properties. The structure displays N-H...N and N-H...S hydrogen bonding. The structure of N'-(pyrrolidine-1-carbonothioyl)picolinohydrazonamide, C 11 H 15 N 5 S, at 100 K has monoclinic (P2 1 /n) symmetry and is also of interest with respect to antibacterial properties. The structure displays N-H...S hydrogen bonding. The structure of (Z)-methyl 2-[amino(pyridin-2-yl)methylidene]-1-methylhydrazinecarbodithioate, C 9 H 13 N 4 S 2 , has triclinic (P-1) symmetry. The structure displays N-H...S hydrogen bonding.

The search for new tuberculostatics is important considering the occurrence of drug-resistant strains of Mycobacterium tuberculosis. Three polymorphs of N'-(1,3-dithiolan-2-ylidene)-4-nitrobenzohydrazide (a potentially tuberculostatic agent), C 10 H 9 N 3 O 3 S 2 , denoted (I1), (I2) and (I3), and the monohydrate of this compound, C 10 H 9 N 3 O 3 S 2 ·H 2 O, (I4), have been characterized by single-crystal X-ray diffraction. The conformations of the molecules in all these structures are very similar. Structures (I1), (I2) and (I3) provide an example of packing polymorphism resulting from different intermolecular interactions.

The structural resemblance between the fused imidazopyridine heterocyclic ring system and purines has prompted biological investigations to assess their potential therapeutic significance. They are known to play a crucial role in numerous disease conditions. The discovery of their first bioactivity as GABA A receptor positive allosteric modulators divulged their medicinal potential. Proton pump inhibitors, aromatase inhibitors, and NSAIDs were also found in this chemical group. Imidazopyridines have the ability to influence many cellular pathways necessary for the proper functioning of cancerous cells, pathogens, components of the immune system, enzymes involved in carbohydrate metabolism, etc. The collective results of biochemical and biophysical properties foregrounded their medicinal significance in central nervous system, digestive system, cancer, inflammation, etc. In recent years, new preparative methods for the synthesis of imidazopyridines using various catalysts have been described. The present manuscript to the best of our knowledge is the complete compilation on the synthesis and medicinal aspects of imidazo[4,5- b ]pyridines and imidazo[4,5- c ]pyridines reported from the year 2000 to date, including structure-activity relationships.

Searches for new tuberculostatic agents are important considering the occurrence of drug-resistant strains of Mycobacterium tuberculosis. The structures of three new potentially tuberculostatic compounds, namely isopropyl methyl (2-hydroxybenzoyl)carbonohydrazonodithioate, C 12 H 16 N 2 O 2 S 2 , (Z)-benzyl methyl (2-hydroxybenzoyl)carbonohydrazonodithioate, C 16 H 16 N 2 O 2 S 2 , and dibenzyl (2-hydroxybenzoyl)carbonohydrazonodithioate propan-2-ol monosolvate, C 22 H 20 N 2 O 2 S 2 ·C 3 H 8 O, were determined by X-ray diffraction. The mutual orientation of the three main fragments of the compounds, namely an aromatic ring, a dithioester group and a hydrazide group, can influence the biological activity of the compounds. In all three of the structures studied, the C(=O)NH group is in the anti conformation. In addition, the presence of the hydroxy group in the ortho position of the aromatic ring in all three structures leads to the formation of an intramolecular hydrogen bond stabilizing the planarity of the molecules.

The emergence of drug-resistant strains of Mycobacterium tuberculosis has intensified efforts to identify new lead tuberculostatics. Our earlier studies concluded that the planarity of a molecule correlates well with its tuberculostatic activity. According to our hypothesis, only derivatives whose molecules are capable of adopting a planar conformation may show tuberculostatic activity. The structures of three new potentially tuberculostatic compounds, namely N'-[bis(methylsulfanyl)methylidene]-N-methyl-4-nitrobenzohydrazide (denoted G1), C11H13N3O3S2, N'-[bis(benzylsulfanyl)methylidene]-N-methyl-4-nitrobenzohydrazide (denoted G2), C23H21N3O3S2, and N'-[(benzylsulfanyl)(methylsulfanyl)methylidene]-4-nitrobenzohydrazide (denoted G3), C16H15N3O3S2, were determined by X-ray diffraction. The significant distortion from planarity caused by the methyl substituent at the N atom of the hydrazide group or the NO2 substituent in the aromatic ring leads to the loss of tuberculostatic activity for G1, G2 and G4 {systematic name: N'-[bis(methylsulfanyl)methylidene]-2-nitrobenzohydrazide}. A similar effect is observed when there are large substituents at the S atoms (G2 and G3).

A series of novel 2-(2-phenalkyl)-1H-benzo[d]imidazole derivatives and analogues (2a-3l) have been synthesized and evaluated for tuberculostatic activity. Benzimidazoles substituted at the C-2 position with phenethyl, styryl and 3,5-dichlorophenethyl moiety were obtained. Compounds 2g, 2h and 2i bearing methyl groups at the benzimidazole system and phenalkyl substituent at the C-2 position showed high tuberculostatic activity against Mycobacterium tuberculosis strains with MIC values ranging from 0.8 to 6.2 μg/mL (2.5-25 μM). More importantly, derivatives 2g (5,6-dimethyl-2-phenethyl-1H-benzo[d]imidazole) and 2i (2-(3,5-dichlorophenethyl)-5,6-dimethyl-1H-benzo[d]imidazole) appeared selective for M. tuberculosis as compared with eukaryotic cells: non-malignant (neonatal human dermal fibroblasts) and malignant (mouse melanoma B16-F10 cell line). These compounds may thus represent a novel, selective class of anti-tubercular agents. SAR studies resulted in interesting conclusions on structural factors affecting tuberculostatic activity., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

A series of novel 1H-benzo[d]imidazole derivatives and analogues (1-25) have been synthesized and evaluated for tuberculostatic activity. Benzimidazoles substituted at the C-2 position with cyclohexylethyl, cyclohexylpropyl and phenylpropyl moiety or 4-phenylpyridine system were obtained. Compounds 3, 4, 6 and 7 bearing halogen atoms or methyl groups at the benzimidazole system and cyclohexylethyl substituent at the C-2 position showed an excellent tuberculostatic activity against Mycobacterium tuberculosis and Mycobacterium bovis strains with MIC values ranging from 0.75 to 1.5 μg/mL. More importantly, derivatives 4 (5-Bromo-2-(2-cyclohexylethyl)-1H-benzo[d]imidazole) and 6 (2-(2-cyclohexylethyl)-5,6-dimethyl-1H-benzo[d]imidazole) appeared selective for M. tuberculosis and M. bovis as compared with non-malignant eukaryotic cells (LLC-PK1 pig kidney epithelial cell line). These compounds may thus represent a novel, selective class of anti-tubercular agents., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Abstract: A series of novel 1,2,4-thiadiazine 1,1-dioxides were synthesized by condensation of 2-chlorobenzenesulfonamide and 4-chloropyridine-3-sulfonamide with heterocyclic methyl carbimidates obtained from heterocyclic carbonitriles and used at the time of their creation. Substituted amidines were isolated as the intermediates in the reaction with 2-chlorobenzenesulfonamide. Those intermediates were successfully cyclized to corresponding 1,2,4-thiadiazine 1,1-dioxides in pyridine with the addition of DBU. The newly synthesized compounds were evaluated for their tuberculostatic and anticancer activities. Eight compounds were able to inhibit the growth of some renal and non-small cell lung cancer cell lines.

Abstract: A series of novel heterocyclic sulfonyl-carboximidamides were synthesized in satisfactory yields via condensation of heterocyclic methyl carbimidates with 2-chlorobenzenesulfonamide and 4-chloropyridine-3-sulfonamide. New structures were confirmed by IR and NMR spectra as well as elemental analyses. X-ray crystallography of two derivatives was performed. The single-crystal structures confirmed the presence of a primary amine group in the amidine moiety. All the compounds were screened for their tuberculostatic, antibacterial, and anticancer activities. Preliminary results indicated that target compounds exhibited weak tuberculostatic and antibacterial activities. Seven compounds inhibited the growth of some cancer cell lines, whereas one of the 2-quinoline derivatives displayed favorable activity against all tested cancer cells with GI 50 values of 0.92-13 μM.

A series of novel heterocyclic sulfamoyl-phenyl-carboximidamides were synthesized in satisfactory yields via condensation of clinically applied sulfonamides with heterocyclic methyl carbimidates. New structures were confirmed by IR and NMR spectra as well as elemental analyses. All the compounds were screened for their antibacterial, antifungal, and tuberculostatic activities. Preliminary results indicated that some target compounds exhibited promising antibacterial potency. Especially, N-[4-(thiazol-2-sulfamoyl)phenyl]pyrazine-2-carboximidamide (16) was found to be as potent as clinically applied sulfamethoxypyridazine., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Methyl 2-(3,4-dichlorobenzoyl)-1-methylhydrazinecarbodithioate, C(10)H(10)Cl(2)N(2)OS(2), (F1), butyl 2-(3,4-dichlorobenzoyl)-1-methylhydrazinecarbodithioate, C(13)H(16)Cl(2)N(2)OS(2), (F2), and 3,4-dichloro-N-(2-sulfanylidene-1,3-thiazinan-3-yl)benzamide, C(11)H(10)Cl(2)N(2)OS(2), (F3), were studied by X-ray diffraction to test our hypothesis that planarity of aryloylhydrazinedithiocarbazic acid esters is a prerequisite for tuberculostatic activity. All compounds examined in this study are inactive and nonplanar due to twists along two specific bonds in the central frame of the molecules. The significant twist at the N-N bond, with an C-N-N-C(S) torsion angle of about 85°, results from repulsion caused by a methyl substituent at the N' atom of the hydrazide group. The other twist is that within the benzoyl group at the C(O)-Ph bond, i.e. the N-C(=O)-C(phenyl)-C torsion angle: the values found in the studied structures (25-30°) are in agreement with those observed in other compounds containing a similar fragment. As some nonplanar benzoyl derivatives are active, it seems that planarity of the hydrazinedithioate fragment is more important for tuberculostatic activity than planarity of the aryloyl group.

Dimethyl (3,4-dichlorobenzoyl)carbonohydrazonodithioate, C(10)H(10)Cl(2)N(2)OS(2), (D1), dibenzyl (3,4-dichlorobenzoyl)carbonohydrazonodithioate, C(22)H(18)Cl(2)N(2)OS(2), (D2), dimethyl (3,4-dichlorobenzoyl)-1-methylcarbonohydrazonodithioate, C(11)H(12)Cl(2)N(2)OS(2), (D3), 3,4-dichloro-N'-(1,3-dithiolan-2-ylidene)-N-methylbenzohydrazide, C(11)H(10)Cl(2)N(2)OS(2), (D4), were synthesized as potential tuberculostatics. Compound (D1) (with two molecules in the asymmetric unit) was the only one showing tuberculostatic activity of the same range as the common drugs isoniazid and pyrazinamide. The molecular structures of the studied compounds depend on the substitution at the N atom adjacent to the carbonyl group. In the case of the unsubstituted derivatives (D1) and (D2), their central frames are generally planar with a twist of the 3,4-dichlorophenyl ring by 30-40°. Until now, coplanarity of the aromatic ring with the (methylene)carbonohydrazone fragment has been considered a prerequisite for tuberculostatic activity. The N-methylated derivatives (D3) and (D4) show an additional twist along the N-C(=O) bond by 20-30° due to the spatial repulsion introduced by the methyl substituent.

Abstract: A series of novel S -esters of 2-(4-nitrobenzoyl)hydrazinecarbodithioic acid and S , S' -diesters of (4-nitrobenzoyl)carbonohydrazonodithioic acid were synthesized by reaction of 4-nitrobenzohydrazide and N -methyl-4-nitrobenzohydrazide with carbon disulfide and alkyl halides in the presence of triethylamine. Novel 5-(4-nitrophenyl)-1,3,4-oxadiazoles were also obtained. The structures were confirmed by IR, NMR, and mass spectroscopy, and by elemental analysis. All the compounds obtained were screened in vitro for their tuberculostatic activity. Promising preliminary results were obtained for some of the compounds. The crystal structure of the most active compound was determined.

Abstract: A series of novel phenylsulfonyl- and 4-aminophenylsulfonyl-carboximidamides were synthesized by condensation of sulfonamides with heterocyclic methyl carbimidates obtained from heterocyclic carbonitriles and used 'at its inception.' The molecular structure of the obtained compounds is discussed. Compounds possessing heterocyclic systems with a nitrogen atom in the α position to the functional group showed a different single-crystal structure than expected. The synthesized derivatives were evaluated for antimicrobial activities: tuberculostatic, antibacterial, and antifungal., Graphical Abstract: .

A series of novel 3-cyclohexylpropanoic acid derivatives and 3-cyclohexylpropanoic acid-derived nitrogen heterocyclic compounds (1-8) have been synthesized and evaluated for tuberculostatic activity. Compounds 1a, 1c, 1e and 1f bearing benzimidazole or benzimidazole-like systems showed the most potent tuberculostatic activity against Mycobacterium tuberculosis strains with MIC values ranging from 1.5 to 12.5μg/mL. More importantly 1a (6-chloro-2-(2-cyclohexylethyl)-4-nitro-1H-benzo[d]imidazole) and 1f (2-(2-cyclohexylethyl)-1H-imidazo[4,5-b]phenazine) appeared selective for M. tuberculosis as compared with eukaryotic cells (human fibroblasts), and other antimicrobial strains. These compounds may thus represent a novel, selective class of antitubercular agents. Additionally compound 1a stimulated type I collagen output by fibroblasts, in vitro., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Methyl 2-(pyrazin-2-ylcarbonyl)hydrazinecarbodithioate, C(7)H(8)N(4)OS(2), (E1), N'-[bis(methylsulfanyl)methylidene]pyrazine-2-carbohydrazide, C(8)H(10)N(4)OS(2), (F1), N'-[bis(methylsulfanyl)methylidene]-6-methoxypyrazine-2-carbohydrazide, C(9)H(12)N(4)O(2)S(2), (F2), and methyl 1-methyl-2-(pyrazin-2-ylcarbonyl)hydrazinecarbodithioate, C(8)H(10)N(4)OS(2), (G1), can be considered as derivatives of classical (thio)amide-type tuberculostatics, and all are moderately active against Mycobacterium tuberculosis. This study was undertaken in a search for relationships between activity and specific intramolecular interactions, especially conjugations and hydrogen-bond contacts, and the molecular structures were compared with respective amine analogues, also active against the pathogen. Despite the differences between the amine and carbonyl groups with opposite functions in the hydrogen bond, the two types of structure show a surprisingly similar planar geometry, mostly due to the conjugations aided by the bifurcated intramolecular hydrogen-bond contact between the N-H group of the central hydrazide group as donor and a pyrazine N atom and an S atom of the dithio function as acceptors. Planarity was suggested to be crucial for the tuberculostatic activity of these compounds. The N-methylated derivative (G1) showed a significant twist at the N-N bond [torsion angle = -121.9 (3)°] due to the methyl substitution, which precludes an intramolecular N-H···S contact and the planarity of the whole molecule. Nonetheless, the compound shows moderate tuberculostatic activity., (© 2011 International Union of Crystallography)

Four compounds showing moderate antituberculostatic activity have been studied to test the hypothesis that the planarity of the 2-[amino(pyrazin-2-yl)methylidene]dithiocarbazate fragment is crucial for activity. N'-Anilinopyrazine-2-carboximidamide, C(11)H(11)N(5), D1, and diethyl 2,2'-[({[amino(pyrazin-2-yl)methylidene]hydrazinylidene}methylidene)bis(sulfanediyl)]diacetate, C(14)H(19)N(5)O(4)S(2), B1, maintain planarity due to conjugation and attractive intramolecular hydrogen-bond contacts, while methyl 3-[amino(pyrazin-2-yl)methylidene]-2-methyldithiocarbazate, C(8)H(11)N(5)S(2), C1, and benzyl 3-[amino(pyrazin-2-yl)methylidene]-2-methyldithiocarbazate, C(14)H(15)N(5)S(2), C2, are not planar, due to methylation at one of the N atoms of the central N-N bond. The resulting twists of the two molecular halves (parts) of C1 and C2 are indicated by torsion angles of 116.5 (2) and -135.9 (2)°, respectively, compared with values of about 180° in the crystal structures of nonsubstituted compounds. As the methylated derivatives show similar activity against Mycobacterium tuberculosis to that of the nonsubstituted derivatives, maintaining planarity does not seem to be a prerequisite for activity.

Abstract: New dimethyl benzoylcarbonohydrazonodithioates were obtained by CS 2 addition to arylcarboxylic acid hydrazides and methylation of the formed adduct. The new derivatives were tested for their activity against Mycobacterium tuberculosis . Some compounds exhibited high activity toward sensitive and resistant strains.

The new pyrazine derivatives exhibiting an antibacterial activity have been synthesized. Initial amidoxime 1 was obtained in the reaction of pyrazinecarbonitrile with hydroxylamine. Upon treatment of amidoxime with methyl iodide O-methyl derivative 2 was formed. Both amidoximes were transformed into imidoyl chlorides 3, 4. Then the chloride atom in those derivatives was substituted with various secondary amines giving appropriate oximes 5-18 and O-methyl-oximes 19 and 20. The obtained compounds were tested in vitro for their tuberculostatic activity. The inhibiting concentration (MIC) values were within 25-100 microg/mL. Their activity towards 25 strains of anaerobic and 25 strains of aerobic bacteria was also studied. Three compounds exhibited activity against both types of bacteria.

Synthetic antitumor anthracenedione drugs, in contrast to anthracycline antibiotics, are ineffective in free radical formation in NADH dehydrogenase system. Our results have indicated that neither the reduction potential nor the side chain conformation and the energies of border orbitals (HOMO and LUMO) determine the ability of anthracenediones to stimulate reactive oxygen species formation in NADH dehydrogenase system. It was shown that the distribution of the molecular electrostatic potential (MEP), around the quinone system was crucial for this ability. We have found for non-stimulating anthracenediones that the clouds of positive MEP cover the quinone carbon atoms while for agents effective in stimulating reactive oxygen species formation the clouds of negative MEP cover continuously the aromatic core together with the quinone system.

Anthraquinone compounds belong to the most important class of clinical antitumour agents. However, their use is limited by their peroxidating activity, being the consequence of free radical formation initiated by three oxyreductases. This activity is considered to be the main cause of cardiotoxic effects. The affinity of anthraquinone compounds to these enzymes is an essential factor governing the rate of one-electron transfer and the generation of oxygen radicals. A series of novel derivatives and analogues of natural and synthetic anthraquinones has been examined with the aim of identifying the structural factors essential for the ability to stimulate oxygen radical formation catalysed by NADH dehydrogenase. Functional groups and moieties favouring or disfavouring the interaction of the compounds with the enzyme have been determined. The quinonoid moiety as well as at least two phenolic groups in peri positions favoured the affinity of these compounds for NADH dehydrogenase. The modification of the quinonoid structure to iminoquinonoid or carboquinonoid forms dramatically decreased interaction with the enzyme. The O'-substitution by a bulky group in the sugar moiety of daunorubicin decreased the ability of the derivatives to stimulate oxygen radical formation. It has also been shown that the presence of an ionizable amino group on the sugar moiety of daunorubicin favours interaction with the NADH dehydrogenase. However, its location is not essential for this effect.