Most cited article - PubMed ID 25587786
Novel pyrazine analogs of chalcones: synthesis and evaluation of their antifungal and antimycobacterial activity
The greatest threat and medicinal impact within gram-positive pathogens are posed by two bacterial genera, Staphylococcus and Enterococcus. Chalcones have a wide range of biological activities and are recognized as effective templates in medicinal chemistry. This study provides comprehensive insight into the anti-staphylococcal and anti-enterococcal activities of two recently published brominated and chlorinated pyrazine-based chalcones, CH-0y and CH-0w. Their effects against 4 reference and 12 staphylococcal and enterococcal clinical isolates were evaluated. Bactericidal action, the activity in combination with selected conventional antibiotics, the study of post-antimicrobial effect (PAE, PAE/SME), and in vitro and in vivo toxicity, were included. In CH-0y, anti-staphylococcal activity ranging from MIC = 15.625 to 62.5 μM, and activity against E. faecium from 31.25 to 62.5 μM was determined. In CH-0w, anti-staphylococcal activity ranging from 31.25 to 125 μM, and activity against E. faecium and E. faecalis (62.5 μM) was revealed. Both CH-0y and CH-0w showed bactericidal action, beneficial impact on bacterial growth delay within PAE and PAE/SME studies, and non/low toxicity in vivo. Compared to CH-0w, CH-0y seems to have higher anti-staphylococcal and less toxic potential. In conclusion, chalcones CH-0y and CH-0w could be considered as structural pattern for future adjuvants to selected antibiotic drugs.
Chalcones are polyphenolic secondary metabolites of plants, many of which have antioxidant activity. Herein, a set of 26 synthetic chalcone derivatives with alkyl substituted pyrazine heterocycle A and four types of the monophenolic ring B, were evaluated for the potential radical scavenging and antioxidant cellular capacity influencing the growth of cells exposed to H₂O₂. Before that, compounds were screened for cytotoxicity on THP-1 and HepG2 cell lines. Most of them were not cytotoxic in an overnight MTS assay. However, three of them, 4a, 4c and 4e showed 1,1-diphenyl-2-picrylhydrazyl (DPPH●) radical scavenging activity, through single electron transfer followed by a proton transfer (SET-PT) mechanism as revealed by density functional theory (DFT) modeling. DFT modeling of radical scavenging mechanisms was done at the SMD//(U)M052X/6-311++G** level. The in vitro effects of 4a, 4c and 4e on the growth of THP-1 cells during four days pre- or post-treatment with H₂O₂ were examined daily with the trypan blue exclusion assay. Their various cellular effects reflect differences in their radical scavenging capacity and molecular lipophilicity (clogP) and depend upon the cellular redox status. The applied simple in vitro-in silico screening cascade enables fast identification and initial characterization of potent radical scavengers.
- Keywords
- DFT, antioxidant, chalcone-like, in silico, in vitro, pyrazine, radical scavenging,
- Publication type
- Journal Article 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
Chalcones, i.e., compounds with the chemical pattern of 1,3-diphenylprop-2-en-1-ones, exert a wide range of bio-activities, e.g., antioxidant, anti-inflammatory, anticancer, anti-infective etc. Our research group has been focused on pyrazine analogues of chalcones; several series have been synthesized and tested in vitro on antifungal and antimycobacterial activity. The highest potency was exhibited by derivatives with electron withdrawing groups (EWG) in positions 2 and 4 of the ring B. As halogens also have electron withdrawing properties, novel halogenated derivatives were prepared by Claisen-Schmidt condensation. All compounds were submitted for evaluation of their antifungal and antibacterial activity, including their antimycobacterial effect. In the antifungal assay against eight strains of selected fungi, growth inhibition of Candida glabrata and Trichophyton interdigitale (formerly T. mentagrophytes) was shown by non-alkylated derivatives with 2-bromo or 2-chloro substitution. In the panel of selected bacteria, 2-chloro derivatives showed the highest inhibitory effect on Staphylococcus sp. In addition, all products were also screened for their antimycobacterial activity against Mycobacterium tuberculosis H37RV My 331/88, M. kansasii My 235/80, M. avium 152/80 and M. smegmatis CCM 4622. Some of the examined compounds, inhibited growth of M. kansasii and M. smegmatis with minimum inhibitory concentrations (MICs) comparable with those of isoniazid.
- Keywords
- antibacterial, antifungal, antimycobacterial, chalcone, halogenated, pyrazine,
- MeSH
- Anti-Infective Agents * chemical synthesis chemistry pharmacology MeSH
- Candida glabrata growth & development MeSH
- Chalcone * chemical synthesis chemistry pharmacology MeSH
- Hydrocarbons, Halogenated * chemical synthesis chemistry pharmacology MeSH
- Mycobacterium growth & development MeSH
- Pyrazines * chemical synthesis chemistry pharmacology MeSH
- Trichophyton growth & development MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Anti-Infective Agents * MeSH
- Chalcone * MeSH
- Hydrocarbons, Halogenated * MeSH
- Pyrazines * MeSH
A series of N-alkyl-3-(alkylamino)pyrazine-2-carboxamides and their N-alkyl-3-chloropyrazine-2-carboxamide precursors were prepared. All compounds were characterized by analytical methods and tested for antimicrobial and antiviral activity. The antimycobacterial MIC values against Mycobacterium tuberculosis H37Rv of the most effective compounds, 3-(hexylamino)-, 3-(heptylamino)- and 3-(octylamino)-N-methyl-pyrazine-2-carboxamides 14‒16, was 25 μg/mL. The compounds inhibited photosystem 2 photosynthetic electron transport (PET) in spinach chloroplasts. This activity was strongly connected with the lipophilicity of the compounds. For effective PET inhibition longer alkyl chains in the 3-(alkylamino) substituent in the N-alkyl-3-(alkylamino)pyrazine-2-carboxamide molecule were more favourable than two shorter alkyl chains.
- Keywords
- alkylation, aminodehalogenation, antimycobacterial activity, inhibition of photosynthetic electron transport, pyrazinamide, pyrazine, structure-activity relationships,
- MeSH
- Antitubercular Agents chemical synthesis pharmacology MeSH
- Bacterial Proteins antagonists & inhibitors metabolism MeSH
- Chloroplasts metabolism MeSH
- Microbial Sensitivity Tests MeSH
- Mycobacterium tuberculosis drug effects metabolism MeSH
- Pyrazinamide chemical synthesis chemistry pharmacology MeSH
- Pyrazines chemical synthesis pharmacology MeSH
- Spinacia oleracea metabolism MeSH
- Fatty Acid Synthases antagonists & inhibitors metabolism 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
- Antitubercular Agents MeSH
- Bacterial Proteins MeSH
- fatty acid synthase I, mycobacteria MeSH Browser
- Pyrazinamide MeSH
- Pyrazines MeSH
- Fatty Acid Synthases MeSH
