Molecular structures and in Silico molecular docking of new pyrazine-based heterocycles as antibacterial agents
Abstract Compound 2-(2-cyanoacetamido)pyrazine (3) serves as a key precursor for synthesizing various new pyrazine-linked heterocycles, including pyridine, thiazole, pyrazole, chromene, and pyrazolotriazine derivatives. Pyrazine-pyridone analogues 5a-d were obtained by reacting compound 3 with subst...
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2025-06-01
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| Online Access: | https://doi.org/10.1186/s13065-025-01535-w |
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| author | Mohamed R. Elmorsy Sara H. Yousef Ehab Abdel-Latif Safa A. Badawy |
| author_facet | Mohamed R. Elmorsy Sara H. Yousef Ehab Abdel-Latif Safa A. Badawy |
| author_sort | Mohamed R. Elmorsy |
| collection | DOAJ |
| description | Abstract Compound 2-(2-cyanoacetamido)pyrazine (3) serves as a key precursor for synthesizing various new pyrazine-linked heterocycles, including pyridine, thiazole, pyrazole, chromene, and pyrazolotriazine derivatives. Pyrazine-pyridone analogues 5a-d were obtained by reacting compound 3 with substituted 2-(arylidene)malononitriles (4a–d). Substituted pyrazine-thiazoles (8 and 9) were synthesized by condensation with phenyl isothiocyanate, followed by cyclization using ethyl bromoacetate or chloroacetone. Pyrazine-chromenes (14, 15) and pyrazine-naphthoxazines (16, 17) were prepared by reacting salicylaldehyde and naphthol derivatives. Additionally, pyrazine-pyrazolotriazines 19a and 19b were formed by coupling diazotized aminopyrazoles (18a and 18b). The structures of the synthesized compounds were confirmed using IR, 1HNMR, and 13C NMR spectroscopy. Antibacterial activity was evaluated against gram-positive (S. aureus and B. subtilis) and gram-negative (E. coli and K. pneumoniae) bacteria. Notably, compound 5c exhibited strong activity against E. coli (15 mm), and 5d showed potent inhibition against S. aureus (18 mm), comparable to the reference antibiotic gentamicin. Molecular docking studies revealed that pyrazine-pyridone derivative 5d displayed the highest binding affinity (S = -7.4519 kcal/mol, RMSD = 1.2498), attributed to two key interactions: one hydrogen-donor and one π-hydrogen bond with the bacterial target (PDB: 4DUH). These in silico findings suggest that 5d can effectively bind to a critical bacterial enzyme, reinforcing its potential as a promising antibacterial agent. Moreover, the Swiss ADME study provides an in-depth analysis of the drug-like properties and pharmacokinetic attributes of these compounds, further supporting their potential for drug development. Overall, compound 5d was the most promising candidate for further antibacterial drug design and optimization. |
| format | Article |
| id | doaj-art-d09aaa8a8ed54a6d8c516feac96f73ed |
| institution | OA Journals |
| issn | 2661-801X |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Chemistry |
| spelling | doaj-art-d09aaa8a8ed54a6d8c516feac96f73ed2025-08-20T02:06:23ZengBMCBMC Chemistry2661-801X2025-06-0119111510.1186/s13065-025-01535-wMolecular structures and in Silico molecular docking of new pyrazine-based heterocycles as antibacterial agentsMohamed R. Elmorsy0Sara H. Yousef1Ehab Abdel-Latif2Safa A. Badawy3Department of Chemistry, Faculty of Science, Mansoura UniversityDepartment of Chemistry, Faculty of Science, Mansoura UniversityDepartment of Chemistry, Faculty of Science, Mansoura UniversityDepartment of Chemistry, Faculty of Science, Mansoura UniversityAbstract Compound 2-(2-cyanoacetamido)pyrazine (3) serves as a key precursor for synthesizing various new pyrazine-linked heterocycles, including pyridine, thiazole, pyrazole, chromene, and pyrazolotriazine derivatives. Pyrazine-pyridone analogues 5a-d were obtained by reacting compound 3 with substituted 2-(arylidene)malononitriles (4a–d). Substituted pyrazine-thiazoles (8 and 9) were synthesized by condensation with phenyl isothiocyanate, followed by cyclization using ethyl bromoacetate or chloroacetone. Pyrazine-chromenes (14, 15) and pyrazine-naphthoxazines (16, 17) were prepared by reacting salicylaldehyde and naphthol derivatives. Additionally, pyrazine-pyrazolotriazines 19a and 19b were formed by coupling diazotized aminopyrazoles (18a and 18b). The structures of the synthesized compounds were confirmed using IR, 1HNMR, and 13C NMR spectroscopy. Antibacterial activity was evaluated against gram-positive (S. aureus and B. subtilis) and gram-negative (E. coli and K. pneumoniae) bacteria. Notably, compound 5c exhibited strong activity against E. coli (15 mm), and 5d showed potent inhibition against S. aureus (18 mm), comparable to the reference antibiotic gentamicin. Molecular docking studies revealed that pyrazine-pyridone derivative 5d displayed the highest binding affinity (S = -7.4519 kcal/mol, RMSD = 1.2498), attributed to two key interactions: one hydrogen-donor and one π-hydrogen bond with the bacterial target (PDB: 4DUH). These in silico findings suggest that 5d can effectively bind to a critical bacterial enzyme, reinforcing its potential as a promising antibacterial agent. Moreover, the Swiss ADME study provides an in-depth analysis of the drug-like properties and pharmacokinetic attributes of these compounds, further supporting their potential for drug development. Overall, compound 5d was the most promising candidate for further antibacterial drug design and optimization.https://doi.org/10.1186/s13065-025-01535-wPyrazine-based heterocyclesAntibacterial activityMolecular dockingIn silico ADME analysisStructure–activity relationship (SAR) |
| spellingShingle | Mohamed R. Elmorsy Sara H. Yousef Ehab Abdel-Latif Safa A. Badawy Molecular structures and in Silico molecular docking of new pyrazine-based heterocycles as antibacterial agents BMC Chemistry Pyrazine-based heterocycles Antibacterial activity Molecular docking In silico ADME analysis Structure–activity relationship (SAR) |
| title | Molecular structures and in Silico molecular docking of new pyrazine-based heterocycles as antibacterial agents |
| title_full | Molecular structures and in Silico molecular docking of new pyrazine-based heterocycles as antibacterial agents |
| title_fullStr | Molecular structures and in Silico molecular docking of new pyrazine-based heterocycles as antibacterial agents |
| title_full_unstemmed | Molecular structures and in Silico molecular docking of new pyrazine-based heterocycles as antibacterial agents |
| title_short | Molecular structures and in Silico molecular docking of new pyrazine-based heterocycles as antibacterial agents |
| title_sort | molecular structures and in silico molecular docking of new pyrazine based heterocycles as antibacterial agents |
| topic | Pyrazine-based heterocycles Antibacterial activity Molecular docking In silico ADME analysis Structure–activity relationship (SAR) |
| url | https://doi.org/10.1186/s13065-025-01535-w |
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