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.

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.

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.

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.

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.

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.