Series of seventeen new multihalogenated 1-hydroxynaphthalene-2-carboxanilides was prepared and characterized. All the compounds were tested for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. 1-Hydroxy-N-phenylnaphthalene-2-carboxamides substituted in the anilide part by 3,5-dichloro-, 4-bromo-3-chloro-, 2,5-dibromo- and 3,4,5-trichloro atoms were the most potent PET inhibitors (IC50 = 5.2, 6.7, 7.6 and 8.0 µM, respectively). The inhibitory activity of these compounds depends on the position and the type of halogen substituents, i.e., on lipophilicity and electronic properties of individual substituents of the anilide part of the molecule. Interactions of the studied compounds with chlorophyll a and aromatic amino acids present in pigment-protein complexes mainly in PS II were documented by fluorescence spectroscopy. The section between P680 and plastoquinone QB in the PET chain occurring on the acceptor side of PS II can be suggested as the site of action of the compounds. The structure-activity relationships are discussed.

• Keywords
• hydroxynaphthalene-carboxamides, photosynthetic electron transport (PET) inhibition, spinach chloroplasts, structure-activity relationships,
• MeSH
• Chloroplasts drug effects   metabolism   MeSH
• Photosynthesis drug effects   MeSH
• Photosystem II Protein Complex metabolism   MeSH
• Inhibitory Concentration 50 MeSH
• Naphthols * chemical synthesis   chemistry   pharmacology   MeSH
• Spinacia oleracea drug effects   metabolism   MeSH
• Electron Transport drug effects   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Photosystem II Protein Complex MeSH
• Naphthols * MeSH

A series of substituted N-benzyl-3-chloropyrazine-2-carboxamides were prepared as positional isomers of 5-chloro and 6-chloro derivatives, prepared previously. During the aminolysis of the acyl chloride, the simultaneous substitution of chlorine with benzylamino moiety gave rise to N-benzyl-3-(benzylamino)pyrazine-2-carboxamides as side products, in some cases. Although not initially planned, the reaction conditions were modified to populate this double substituted series. The final compounds were tested against four mycobacterial strains. N-(2-methylbenzyl)-3-((2-methylbenzyl)amino)pyrazine-2-carboxamide (1a) and N-(3,4-dichlorobenzyl)-3-((3,4-dichlorobenzyl)amino)pyrazine-2-carboxamide (9a) proved to be the most effective against Mycobacterium tuberculosis H37Rv, with MIC = 12.5 μg·mL-1. Compounds were screened for antibacterial activity. The most active compound was 3-chloro-N-(2-chlorobenzyl)pyrazine-2-carboxamide (5) against Staphylococcus aureus with MIC = 7.81 μM, and Staphylococcus epidermidis with MIC = 15.62 μM. HepG2 in vitro cytotoxicity was evaluated for the most active compounds; however, no significant toxicity was detected. Compound 9a was docked to several conformations of the enoyl-ACP-reductase of Mycobacterium tuberculosis. In some cases, it was capable of H-bond interactions, typical for most of the known inhibitors.

• Keywords
• antibacterial activity, antimycobacterial activity, benzylamines, cytotoxicity, enoyl-ACP-reductase, molecular docking, pyrazinamide derivatives,
• MeSH
• Anti-Bacterial Agents chemical synthesis   chemistry   pharmacology   MeSH
• Hep G2 Cells MeSH
• Humans MeSH
• Microbial Sensitivity Tests MeSH
• Molecular Structure MeSH
• Mycobacterium tuberculosis drug effects   MeSH
• Pyrazines chemical synthesis   chemistry   pharmacology   MeSH
• Molecular Docking Simulation MeSH
• Staphylococcus aureus drug effects   MeSH
• Staphylococcus epidermidis drug effects   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anti-Bacterial Agents MeSH
• Pyrazines MeSH

Aminodehalogenation of 3-chloropyrazine-2-carboxamide with variously substituted benzylamines yielded a series of fifteen 3-benzylaminopyrazine-2-carboxamides. Four compounds possessed in vitro whole cell activity against Mycobacterium tuberculosis H37Rv that was at least equivalent to that of the standard pyrazinamide. MIC values ranged from 6 to 42 μM. The best MIC (6 μM) was displayed by 3-[(4-methylbenzyl)amino]pyrazine-2-carboxamide (8) that also showed low cytotoxicity in the HepG2 cell line (IC50 ≥ 250 μM). Only moderate activity against Enterococcus faecalis and Staphylococcus aureus was observed. No activity was detected against any of tested fungal strains. Molecular docking with mycobacterial enoyl-ACP reductase (InhA) was performed to investigate the possible target of the prepared compounds. Active compounds shared common binding interactions of known InhAinhibitors. Antimycobacterial activity of the title compounds was compared to the previously published benzylamino-substituted pyrazines with differing substitution on the pyrazine core (carbonitrile moiety). The title series possessed comparable activity and lower cytotoxicity than molecules containing a carbonitrile group on the pyrazine ring.

• Keywords
• antibacterials, antifungals, benzylamines, cytotoxicity, microwave-assisted, pyrazinamide, tuberculosis,
• MeSH
• Amides chemistry   MeSH
• Anti-Bacterial Agents chemical synthesis   pharmacology   MeSH
• Antifungal Agents chemical synthesis   pharmacology   MeSH
• Anti-Infective Agents chemical synthesis   pharmacology   MeSH
• Antitubercular Agents chemical synthesis   pharmacology   MeSH
• Humans MeSH
• Microbial Sensitivity Tests MeSH
• Molecular Structure MeSH
• Pyrazinamide chemical synthesis   pharmacology   MeSH
• Pyrazines chemistry   MeSH
• Molecular Docking Simulation MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Amides MeSH
• Anti-Bacterial Agents MeSH
• Antifungal Agents MeSH
• Anti-Infective Agents MeSH
• Antitubercular Agents MeSH
• Pyrazinamide MeSH
• Pyrazines MeSH

Infectious diseases, such as tuberculosis and invasive mycoses, represent serious health problems. As a part of our long-term efforts to find new agents for the treatment of these diseases, a new series of pyrazine analogs of chalcones bearing an isopropyl group in position 5 of the pyrazine ring was prepared. The structures of the compounds were corroborated by IR and NMR spectroscopy and their purity confirmed by elemental analysis. The susceptibility of eight fungal strains to the studied compounds was tested. The results have been compared with the activity of some previously reported propyl derivatives. The only strain that was susceptible to the studied compounds was Trichophyton mentagrophytes. It was found that replacing a non-branched propyl with a branched isopropyl did not have a decisive and unequivocal influence on the in vitro antifungal activity against T. mentagrophytes. In vitro activity against Trichophyton mentagrophytes comparable with that of fluconazole was exhibited by nitro-substituted derivatives. Unfortunately, no compound exhibited efficacy comparable with that of terbinafine, which is the most widely used agent for treating mycoses caused by dermatophytes. Some of the prepared compounds were assayed for antimycobacterial activity against M. tuberculosis H37Rv. The highest potency was also displayed by nitro-substituted compounds. The results of the present study are in a good agreement with our previous findings and confirm the positive influence of electron-withdrawing groups on the B-ring of chalcones on the antifungal and antimycobacterial activity of these compounds.

• MeSH
• Antifungal Agents chemical synthesis   chemistry   pharmacology   MeSH
• Antitubercular Agents chemical synthesis   chemistry   pharmacology   MeSH
• Chlorocebus aethiops MeSH
• Chalcones chemical synthesis   chemistry   pharmacology   MeSH
• Fungi classification   drug effects   MeSH
• Carbon-13 Magnetic Resonance Spectroscopy MeSH
• Microbial Sensitivity Tests MeSH
• Molecular Structure MeSH
• Mycobacterium tuberculosis drug effects   MeSH
• Proton Magnetic Resonance Spectroscopy MeSH
• Pyrazines chemistry   MeSH
• Spectrophotometry, Infrared MeSH
• Vero Cells MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Antifungal Agents MeSH
• Antitubercular Agents MeSH
• Chalcones MeSH
• Pyrazines MeSH

A series of 18 N-alkyl substituted 3-aminopyrazine-2-carboxamides was prepared in this work according to previously experimentally set and proven conditions using microwave assisted synthesis methodology. This approach for the aminodehalogenation reaction was chosen due to higher yields and shorter reaction times compared to organic reactions with conventional heating. Antimycobacterial, antibacterial, antifungal and photosynthetic electron transport (PET) inhibiting in vitro activities of these compounds were investigated. Experiments for the determination of lipophilicity were also performed. Only a small number of substances with alicyclic side chain showed activity against fungi which was the same or higher than standards and the biological efficacy of the compounds increased with rising lipophilicity. Nine pyrazinamide derivatives also inhibited PET in spinach chloroplasts and the IC50 values of these compounds varied in the range from 14.3 to 1590.0 μmol/L. The inhibitory activity was connected not only with the lipophilicity, but also with the presence of secondary amine fragment bounded to the pyrazine ring. Structure-activity relationships are discussed as well.

• MeSH
• Antifungal Agents chemical synthesis   pharmacology   MeSH
• Antitubercular Agents chemical synthesis   pharmacology   MeSH
• Candida albicans drug effects   MeSH
• Chloroplasts drug effects   metabolism   MeSH
• Photosynthesis drug effects   MeSH
• Herbicides chemical synthesis   pharmacology   MeSH
• Hydrophobic and Hydrophilic Interactions MeSH
• Inhibitory Concentration 50 MeSH
• Microbial Sensitivity Tests MeSH
• Microwaves MeSH
• Mycobacterium tuberculosis drug effects   MeSH
• Pyrazinamide analogs & derivatives   chemical synthesis   pharmacology   MeSH
• Spinacia oleracea drug effects   metabolism   MeSH
• Staphylococcus epidermidis drug effects   MeSH
• Electron Transport drug effects   MeSH
• Structure-Activity Relationship MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Antifungal Agents MeSH
• Antitubercular Agents MeSH
• Herbicides MeSH
• Pyrazinamide MeSH