Most cited article - PubMed ID 21116226
Synthesis, antimycobacterial, antifungal and photosynthesis-inhibiting activity of chlorinated N-phenylpyrazine-2-carboxamides
BACKGROUND AND PURPOSE: New compounds and innovative therapeutic approaches are trying to prevent antimicrobial resistance, which has become a global health challenge. EXPERIMENTAL APPROACH: This study includes a series of twelve mono-, di- and trichlorinated 1-hydroxynaphthalene-2-carboxanilides designed as multitarget agents. All compounds were evaluated for their antistaphylococcal activity. Furthermore, MTT assay and chemoproteomic analysis of selected compounds were performed. Cytotoxicity in human cells was also tested. KEY RESULTS: N-(3,5-Dichlorophenyl)-1-hydroxynaphthalene-2-carboxamide (10) demonstrated activity comparable to or higher than clinically used drugs, with minimum inhibitory concentrations (MICs) of 0.37 μM. The compound was equally effective against clinical isolates of methicillin-resistant S. aureus. On the other hand, compound 10 showed 96 % inhibition of S. aureus respiration only at a concentration of 16× MIC. Chemoproteomic analysis revealed that the effect of agent 10 on staphylococci resulted in the downregulation of four proteins. This compound expressed no in vitro cytotoxicity up to a concentration of 30 μM. CONCLUSION: From the set of tested mono-, di- and trisubstituted derivatives, it is evident that the position of chlorine atoms is decisive for significant antistaphylococcal activity. Inhibition of energy metabolism does not appear to be one of the main mechanisms of action of compound 10; on the contrary, the antibacterial effect may likely be contributed by downregulation of proteins (especially ATP-dependent protease ATPase subunit HslU) involved in processes essential for bacterial survival and growth, such as protein, nucleotide/nucleic acid synthesis and efficient protein repair/degradation.
- Keywords
- Lipophilicity, MTT assay, antistaphylococcal activity, chemoproteomic analysis, cytotoxicity,
- Publication type
- Journal Article MeSH
A series of nine 2,3-disubstituted-quinazolin-4(3H)-one derived Schiff bases and their three Cu(II) complexes was prepared and tested for their antimicrobial activities against reference strains Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 and resistant clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis (VRE). All the substances were tested in vitro against Mycobacterium tuberculosis H37Ra ATCC 25177, M. kansasii DSM 44162 and M. smegmatis ATCC 700084. While anti-enterococcal and antimycobacterial activities were insignificant, 3-[(E)-(2-hydroxy-5-nitrobenzylidene)amino]-2-(2-hydroxy-5-nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (SB3) and its Cu(II) complex (SB3-Cu) demonstrated bacteriostatic antistaphylococcal activity. In addition, both compounds, as well as the other two prepared complexes, showed antibiofilm activity, which resulted in a reduction of biofilm formation and eradication of mature S. aureus biofilm by 80% even at concentrations lower than the values of their minimum inhibitory concentrations. In addition, the compounds were tested for their cytotoxic effect on the human monocytic leukemia cell line THP-1. The antileukemic efficiency was improved by the preparation of Cu(II) complexes from the corresponding non-chelated Schiff base ligands.
- Keywords
- Antibacterial activity, Antibiofilm effect, Cu(II) complexes, Cytotoxicity, Quinazolinones, Schiff bases,
- Publication type
- Journal Article MeSH
A series of eighteen 4-chlorocinnamanilides and eighteen 3,4-dichlorocinnamanilides were designed, prepared and characterized. All compounds were evaluated for their activity against gram-positive bacteria and against two mycobacterial strains. Viability on both cancer and primary mammalian cell lines was also assessed. The lipophilicity of the compounds was experimentally determined and correlated together with other physicochemical properties of the prepared derivatives with biological activity. 3,4-Dichlorocinnamanilides showed a broader spectrum of action and higher antibacterial efficacy than 4-chlorocinnamanilides; however, all compounds were more effective or comparable to clinically used drugs (ampicillin, isoniazid, rifampicin). Of the thirty-six compounds, six derivatives showed submicromolar activity against Staphylococcus aureus and clinical isolates of methicillin-resistant S. aureus (MRSA). (2E)-N-[3,5-bis(trifluoromethyl)phenyl]- 3-(4-chlorophenyl)prop-2-enamide was the most potent in series 1. (2E)-N-[3,5-bis(Trifluoromethyl)phenyl]-3-(3,4-dichlorophenyl)prop-2-enamide, (2E)-3-(3,4-dichlorophenyl)-N-[3-(trifluoromethyl)phenyl]prop-2-enamide, (2E)-3-(3,4-dichloro- phenyl)-N-[4-(trifluoromethyl)phenyl]prop-2-enamide and (2E)-3-(3,4-dichlorophenyl)- N-[4-(trifluoromethoxy)phenyl]prop-2-enamide were the most active in series 2 and in addition to activity against S. aureus and MRSA were highly active against Enterococcus faecalis and vancomycin-resistant E. faecalis isolates and against fast-growing Mycobacterium smegmatis and against slow-growing M. marinum, M. tuberculosis non-hazardous test models. In addition, the last three compounds of the above-mentioned showed insignificant cytotoxicity to primary porcine monocyte-derived macrophages.
- Keywords
- antimicrobial activity, cinnamamides, cytotoxicity, lipophilicity, structure-activity relationships,
- MeSH
- Ampicillin pharmacology MeSH
- Anti-Bacterial Agents pharmacology MeSH
- Methicillin-Resistant Staphylococcus aureus * MeSH
- Microbial Sensitivity Tests MeSH
- Mycobacterium tuberculosis * MeSH
- Swine MeSH
- Mammals MeSH
- Staphylococcal Infections * MeSH
- Staphylococcus aureus MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Ampicillin MeSH
- Anti-Bacterial Agents MeSH
A set of twenty-four 3-hydroxynaphthalene-2-carboxanilides, disubstituted on the anilide ring by combinations of methoxy/methyl/fluoro/chloro/bromo and ditrifluoromethyl groups at different positions, was prepared. The compounds were tested for their ability to inhibit photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. N-(3,5-Difluorophenyl)-, N-(3,5-dimethylphenyl)-, N-(2,5-difluorophenyl)- and N-(2,5-dimethylphenyl)-3-hydroxynaphthalene-2-carboxamides showed the highest PET-inhibiting activity (IC50 ~ 10 µM) within the series. These compounds were able to inhibit PET in photosystem II. It has been found that PET-inhibiting activity strongly depends on the position of the individual substituents on the anilide ring and on the lipophilicity of the compounds. The electron-withdrawing properties of the substituents contribute towards the PET activity of these compounds.
- Keywords
- PET inhibition, hydroxynaphthalene-carboxamides, spinach chloroplasts, structure-activity relationships,
- MeSH
- Chloroplasts drug effects metabolism MeSH
- Photosynthesis drug effects MeSH
- Photosystem II Protein Complex antagonists & inhibitors metabolism MeSH
- Herbicides chemistry metabolism MeSH
- Naphthalenes chemistry metabolism 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
- Herbicides MeSH
- Naphthalenes MeSH
Three series of N-(pyrazin-2-yl)benzamides were designed as retro-amide analogues of previously published N-phenylpyrazine-2-carboxamides with in vitro antimycobacterial activity. The synthesized retro-amides were evaluated for in vitro growth inhibiting activity against Mycobacterium tuberculosis H37Rv (Mtb), three non-tuberculous mycobacterial strains (M. avium, M. kansasii, M. smegmatis) and selected bacterial and fungal strains of clinical importance. Regarding activity against Mtb, most N-pyrazinylbenzamides (retro-amides) possessed lower or no activity compared to the corresponding N-phenylpyrazine-2-carboxamides with the same substitution pattern. However, the active retro-amides tended to have lower HepG2 cytotoxicity and better selectivity. Derivatives with 5-chloro substitution on the pyrazine ring were generally more active compared to their 6-cloro positional isomers or non-chlorinated analogues. The best antimycobacterial activity against Mtb was found in N-(5-chloropyrazin-2-yl)benzamides with short alkyl (2h: R² = Me; 2i: R² = Et) in position 4 of the benzene ring (MIC = 6.25 and 3.13 µg/mL, respectively, with SI > 10). N-(5-Chloropyrazin-2-ylbenzamides with hydroxy substitution (2b: R² = 2-OH; 2d: R² = 4-OH) on the benzene ring or their acetylated synthetic precursors possessed the broadest spectrum of activity, being active in all three groups of mycobacterial, bacterial and fungal strains. The substantial differences in in silico calculated properties (hydrogen-bond pattern analysis, molecular electrostatic potential, HOMO and LUMO) can justify the differences in biological activities between N-pyrazinylbenzamides and N-phenylpyrazine-2-carboxamides.
- Keywords
- antibacterial, antifungal, antimycobacterial, cytotoxicity, linker, pyrazinamide, retro-amide, tuberculosis,
- MeSH
- Anti-Bacterial Agents chemical synthesis chemistry pharmacology MeSH
- Benzamides chemical synthesis chemistry pharmacology MeSH
- Cell Line MeSH
- Humans MeSH
- Microbial Sensitivity Tests MeSH
- Models, Molecular MeSH
- Molecular Structure MeSH
- Mycobacterium tuberculosis drug effects MeSH
- Drug Design * MeSH
- Chemistry Techniques, Synthetic * MeSH
- Cell Survival drug effects MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Anti-Bacterial Agents MeSH
- benzamide MeSH Browser
- Benzamides MeSH
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
Two novel thiosemicarbazones and eight novel 2-{[1-(5-alkyl/arylalkylpyrazin-2-yl)ethylidene]hydrazono}-1,3-thiazolidin-4-ones were prepared and tested against a panel of eight fungal strains-Candida albicans ATCC 44859, Candida tropicalis 156, Candida krusei E 28, Candida glabrata 20/I, Trichosporon asahii 1188, Aspergillus fumigatus 231, Lichtheimia corymbifera 272, and Trichophyton interdigitale 445. 1,3-Thiazolidin-4-ones exhibited activity against all strains, the most potent derivative was 2-{[1-(5-butylpyrazin-2-yl)ethylidene]hydrazono}e-1,3-thiazolidin-4-one. Susceptibility of C. glabrata to the studied 1,3-thiazolidin-4-ones (minimum inhibitory concentrations (MICs) were in the range 0.57 to 2.78 mg/L) is of great interest as this opportunistic pathogen is poorly susceptible to azoles and becomes resistant to echinocandins. Antifungal potency of thiosemicarbazones was slightly lower than that of 1,3-thiazolidin-4-ones.
- Keywords
- 1,3-thiazolidin-4-ones, Candida glabrata, acetylpyrazine, antifungal, thiosemicarbazones,
- MeSH
- Antifungal Agents chemical synthesis chemistry pharmacology MeSH
- Aspergillus drug effects MeSH
- Candida drug effects MeSH
- Microbial Sensitivity Tests MeSH
- Molecular Structure MeSH
- Mucorales drug effects MeSH
- Thiazolidinediones chemical synthesis chemistry pharmacology MeSH
- Thiosemicarbazones chemical synthesis chemistry pharmacology MeSH
- Trichophyton drug effects MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Antifungal Agents MeSH
- Thiazolidinediones MeSH
- Thiosemicarbazones 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
In this work a series of 15 N-benzylamine substituted 5-amino-6-methyl-pyrazine-2,3-dicarbonitriles was prepared by the aminodehalogenation reactions using microwave assisted synthesis with experimentally set and proven conditions. This approach for the aminodehalogenation reaction was chosen due to its higher yields and shorter reaction times. The products of this reaction were characterized by IR, NMR and other analytical data. The compounds were evaluated for their antibacterial, antifungal and herbicidal activity. Compounds 3 (R=3,4-Cl), 9 (R=2-Cl) and 11 (R=4-CF3) showed good antimycobacterial activity against Mycobacterium tuberculosis (MIC=6.25 µg/mL). It was found that the lipophilicity is important for antimycobacterial activity and the best substitution on the benzyl moiety of the compounds is a halogen or trifluoromethyl group according to Craig's plot. The activities against bacteria or fungi were insignificant. The presented compounds also inhibited photosynthetic electron transport in spinach chloroplasts and the IC50 values of the active compounds varied in the range from 16.4 to 487.0 µmol/L. The most active substances were 2 (R=3-CF3), 3 (R=3,4-Cl) and 11 (R=4-CF3). A linear dependence between lipophilicity and herbicidal activity was observed.
- MeSH
- Antitubercular Agents chemical synthesis pharmacology MeSH
- Chloroplasts drug effects metabolism MeSH
- Photosynthesis drug effects MeSH
- Halogenation MeSH
- Herbicides chemical synthesis pharmacology MeSH
- Inhibitory Concentration 50 MeSH
- Microbial Sensitivity Tests MeSH
- Microwaves MeSH
- Mycobacterium smegmatis drug effects MeSH
- Mycobacterium tuberculosis drug effects MeSH
- Nitriles chemical synthesis pharmacology MeSH
- Pyrazines chemical synthesis pharmacology MeSH
- Spinacia oleracea drug effects metabolism MeSH
- Electron Transport drug effects MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Antitubercular Agents MeSH
- Herbicides MeSH
- Nitriles MeSH
- Pyrazines MeSH