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.

Pharmacological Potential and Synthetic Approaches of Imidazo[4,5-b]pyridine and Imidazo[4,5-c]pyridine Derivatives.

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 GABAA 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.

Novel 2-(2-phenalkyl)-1H-benzo[d]imidazoles as antitubercular agents. Synthesis, biological evaluation and structure-activity relationship.

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.

Synthesis and evaluation of in vitro antimycobacterial activity of novel 1H-benzo[d]imidazole derivatives and analogues.

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.

Synthesis, structure, and biological activity of novel heterocyclic sulfonyl-carboximidamides.

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 GI50 values of 0.92-13 µM.

Synthesis and biological activity of novel 3-heteroaryl-2H-pyrido[4,3-e][1,2,4]thiadiazine and 3-heteroaryl-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxides.

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.

A novel nucleotide found in human erythrocytes, 4-pyridone-3-carboxamide-1-beta-D-ribonucleoside triphosphate.

We report the identification of a hitherto unknown nucleotide that is present in micromolar concentrations in the erythrocytes of healthy subjects and accumulates at levels comparable with the ATP concentration in erythrocytes of patients with chronic renal failure. The unknown nucleotide was isolated and identified by liquid chromatography with UV and tandem mass detection, (1)H nuclear magnetic resonance and infrared spectroscopy as 4-pyridone-3-carboxamide-1-beta-D-ribonucleoside triphosphate (4PYTP), a structure indicating association with metabolism of the oxidized nicotinamide compounds. Subsequently, we demonstrated formation of 4PYTP in intact human erythrocytes during incubation with the chemically synthesized nucleoside precursor 4-pyridone-3-carboxamide-1-beta-D-ribonucleoside (4PYR). We noted preferential accumulation of monophosphate of 4PYR (4PYMP) over 4PYTP as well as a decrease in erythrocyte ATP concentration during incubation with 4PYR. Both the 4PYR phosphorylation and ATP depletion were blocked by an inhibitor of adenosine kinase. Plasma concentration of 4PYR was detectable but very low (0.013 +/- 0.006 microm) in contrast with the high daily urine excretion of this compound (26.7 +/- 18.2 micromol/24 h) in healthy subjects, indicating much greater renal clearance than other nicotinamide metabolites, nucleosides, or creatinine. We also noted a 40-fold increase in 4PYR plasma concentration in patients with chronic renal failure (0.563 +/- 0.321 microm). We suggest that 4PYTP formation in the erythrocytes is a hitherto unknown process aimed at sequestering potentially toxic 4PYR in a form that could be safely transported and subsequently released and excreted during passage of erythrocytes through the kidney.