Halogenated Pyrrolopyrimidines with Low MIC on <i>Staphylococcus aureus</i> and Synergistic Effects with an Antimicrobial Peptide
Currently, there is a world-wide rise in antibiotic resistance causing burdens to individuals and public healthcare systems. At the same time drug development is lagging behind. Therefore, finding new ways of treating bacterial infections either by identifying new agents or combinations of drugs is...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-07-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/11/8/984 |
| _version_ | 1827601040242900992 |
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| author | Cecilie Elisabeth Olsen Fredrik Heen Blindheim Caroline Krogh Søgaard Lisa Marie Røst Amanda Holstad Singleton Olaug Elisabeth Torheim Bergum Per Bruheim Marit Otterlei Eirik Sundby Bård Helge Hoff |
| author_facet | Cecilie Elisabeth Olsen Fredrik Heen Blindheim Caroline Krogh Søgaard Lisa Marie Røst Amanda Holstad Singleton Olaug Elisabeth Torheim Bergum Per Bruheim Marit Otterlei Eirik Sundby Bård Helge Hoff |
| author_sort | Cecilie Elisabeth Olsen |
| collection | DOAJ |
| description | Currently, there is a world-wide rise in antibiotic resistance causing burdens to individuals and public healthcare systems. At the same time drug development is lagging behind. Therefore, finding new ways of treating bacterial infections either by identifying new agents or combinations of drugs is of utmost importance. Additionally, if combination therapy is based on agents with different modes of action, resistance is less likely to develop. The synthesis of 21 fused pyrimidines and a structure-activity relationship study identified two 6-aryl-7<i>H</i>-pyrrolo [2,3-<i>d</i>] pyrimidin-4-amines with potent activity towards <i>Staphylococcus aureus</i>. The MIC-value was found to be highly dependent on a bromo or iodo substitution in the 4-benzylamine group and a hydroxyl in the <i>meta</i> or <i>para</i> position of the 6-aryl unit. The most active bromo and iodo derivatives had MIC of 8 mg/L. Interestingly, the most potent compounds experienced a four-fold lower MIC-value when they were combined with the antimicrobial peptide betatide giving MIC of 1–2 mg/L. The front runner bromo derivative also has a low activity towards 50 human kinases, including thymidylate monophosphate kinase, a putative antibacterial target. |
| first_indexed | 2024-03-09T04:47:35Z |
| format | Article |
| id | doaj.art-203b81bfb5c3417a9c4c273e9cc60937 |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-09T04:47:35Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-203b81bfb5c3417a9c4c273e9cc609372023-12-03T13:14:00ZengMDPI AGAntibiotics2079-63822022-07-0111898410.3390/antibiotics11080984Halogenated Pyrrolopyrimidines with Low MIC on <i>Staphylococcus aureus</i> and Synergistic Effects with an Antimicrobial PeptideCecilie Elisabeth Olsen0Fredrik Heen Blindheim1Caroline Krogh Søgaard2Lisa Marie Røst3Amanda Holstad Singleton4Olaug Elisabeth Torheim Bergum5Per Bruheim6Marit Otterlei7Eirik Sundby8Bård Helge Hoff9Department of Chemistry, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim, NorwayDepartment of Chemistry, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim, NorwayDepartment of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), NO-7489 Trondheim, NorwayDepartment of Biotechnology and Food Science, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim, NorwayDepartment of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), NO-7489 Trondheim, NorwayDepartment of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), NO-7489 Trondheim, NorwayDepartment of Biotechnology and Food Science, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim, NorwayDepartment of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), NO-7489 Trondheim, NorwayDepartment of Material Science, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim, NorwayDepartment of Chemistry, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim, NorwayCurrently, there is a world-wide rise in antibiotic resistance causing burdens to individuals and public healthcare systems. At the same time drug development is lagging behind. Therefore, finding new ways of treating bacterial infections either by identifying new agents or combinations of drugs is of utmost importance. Additionally, if combination therapy is based on agents with different modes of action, resistance is less likely to develop. The synthesis of 21 fused pyrimidines and a structure-activity relationship study identified two 6-aryl-7<i>H</i>-pyrrolo [2,3-<i>d</i>] pyrimidin-4-amines with potent activity towards <i>Staphylococcus aureus</i>. The MIC-value was found to be highly dependent on a bromo or iodo substitution in the 4-benzylamine group and a hydroxyl in the <i>meta</i> or <i>para</i> position of the 6-aryl unit. The most active bromo and iodo derivatives had MIC of 8 mg/L. Interestingly, the most potent compounds experienced a four-fold lower MIC-value when they were combined with the antimicrobial peptide betatide giving MIC of 1–2 mg/L. The front runner bromo derivative also has a low activity towards 50 human kinases, including thymidylate monophosphate kinase, a putative antibacterial target.https://www.mdpi.com/2079-6382/11/8/984antibacterialpyrrolopyrimidinessynergistic effecthalogenated antibiotic |
| spellingShingle | Cecilie Elisabeth Olsen Fredrik Heen Blindheim Caroline Krogh Søgaard Lisa Marie Røst Amanda Holstad Singleton Olaug Elisabeth Torheim Bergum Per Bruheim Marit Otterlei Eirik Sundby Bård Helge Hoff Halogenated Pyrrolopyrimidines with Low MIC on <i>Staphylococcus aureus</i> and Synergistic Effects with an Antimicrobial Peptide Antibiotics antibacterial pyrrolopyrimidines synergistic effect halogenated antibiotic |
| title | Halogenated Pyrrolopyrimidines with Low MIC on <i>Staphylococcus aureus</i> and Synergistic Effects with an Antimicrobial Peptide |
| title_full | Halogenated Pyrrolopyrimidines with Low MIC on <i>Staphylococcus aureus</i> and Synergistic Effects with an Antimicrobial Peptide |
| title_fullStr | Halogenated Pyrrolopyrimidines with Low MIC on <i>Staphylococcus aureus</i> and Synergistic Effects with an Antimicrobial Peptide |
| title_full_unstemmed | Halogenated Pyrrolopyrimidines with Low MIC on <i>Staphylococcus aureus</i> and Synergistic Effects with an Antimicrobial Peptide |
| title_short | Halogenated Pyrrolopyrimidines with Low MIC on <i>Staphylococcus aureus</i> and Synergistic Effects with an Antimicrobial Peptide |
| title_sort | halogenated pyrrolopyrimidines with low mic on i staphylococcus aureus i and synergistic effects with an antimicrobial peptide |
| topic | antibacterial pyrrolopyrimidines synergistic effect halogenated antibiotic |
| url | https://www.mdpi.com/2079-6382/11/8/984 |
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