Synthesis of Alkyne-Substituted Dihydropyrrolones as Bacterial Quorum-Sensing Inhibitors of <i>Pseudomonas aeruginosa</i>
The Quorum-sensing system in <i>Pseudomonas aeruginosa</i> is responsible for the pathogenicity and the production of virulence factors and biofilm formation. Dihydropyrrolones were previously found to act as inhibitors of QS-dependent bacterial phenotypes. In this study, a range of dihy...
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MDPI AG
2022-01-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/11/2/151 |
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| author | Basmah Almohaywi Tsz Tin Yu George Iskander Shekh Sabir Mohan Bhadbhade David StC. Black Naresh Kumar |
| author_facet | Basmah Almohaywi Tsz Tin Yu George Iskander Shekh Sabir Mohan Bhadbhade David StC. Black Naresh Kumar |
| author_sort | Basmah Almohaywi |
| collection | DOAJ |
| description | The Quorum-sensing system in <i>Pseudomonas aeruginosa</i> is responsible for the pathogenicity and the production of virulence factors and biofilm formation. Dihydropyrrolones were previously found to act as inhibitors of QS-dependent bacterial phenotypes. In this study, a range of dihydropyrrolone (DHP) analogues was synthesized via the lactone-lactam conversion of lactone intermediates followed by the formation of novel acetylene analogues of dihydropyrrolones from brominated dihydropyrrolones via Sonogashira coupling reactions in moderate to high yields. Upon biological testing, the most potent compounds, <b>39</b>–<b>40</b> and <b>44,</b> showed higher bacterial quorum-sensing inhibitory (QSI) activity against <i>P. aeruginosa</i> reporter strain at 62.5 µM. Structure–activity relationship studies revealed that di-alkynyl substituent at the exocyclic position of DHPs possessed higher QSI activities than those of mono-alkynyl DHPs. Moreover, a hexyl-substituent at C3 of DHPs was beneficial to QSI activity while a phenyl substituent at C4 of DHPs was detrimental to QSI activity of analogues. |
| first_indexed | 2024-03-09T22:47:56Z |
| format | Article |
| id | doaj.art-f140969dd3564e1fb30a2eef0962d63a |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-09T22:47:56Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-f140969dd3564e1fb30a2eef0962d63a2023-11-23T18:27:17ZengMDPI AGAntibiotics2079-63822022-01-0111215110.3390/antibiotics11020151Synthesis of Alkyne-Substituted Dihydropyrrolones as Bacterial Quorum-Sensing Inhibitors of <i>Pseudomonas aeruginosa</i>Basmah Almohaywi0Tsz Tin Yu1George Iskander2Shekh Sabir3Mohan Bhadbhade4David StC. Black5Naresh Kumar6Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha 6142, Saudi ArabiaSchool of Chemistry, The University of New South Wales, Sydney, NSW 2052, AustraliaSchool of Chemistry, The University of New South Wales, Sydney, NSW 2052, AustraliaSchool of Chemistry, The University of New South Wales, Sydney, NSW 2052, AustraliaSolid State and Elemental Analysis Unit, Mark Wainwright Analytical Centre, Division of Research, The University of New South Wales, Sydney, NSW 2052, AustraliaSchool of Chemistry, The University of New South Wales, Sydney, NSW 2052, AustraliaSchool of Chemistry, The University of New South Wales, Sydney, NSW 2052, AustraliaThe Quorum-sensing system in <i>Pseudomonas aeruginosa</i> is responsible for the pathogenicity and the production of virulence factors and biofilm formation. Dihydropyrrolones were previously found to act as inhibitors of QS-dependent bacterial phenotypes. In this study, a range of dihydropyrrolone (DHP) analogues was synthesized via the lactone-lactam conversion of lactone intermediates followed by the formation of novel acetylene analogues of dihydropyrrolones from brominated dihydropyrrolones via Sonogashira coupling reactions in moderate to high yields. Upon biological testing, the most potent compounds, <b>39</b>–<b>40</b> and <b>44,</b> showed higher bacterial quorum-sensing inhibitory (QSI) activity against <i>P. aeruginosa</i> reporter strain at 62.5 µM. Structure–activity relationship studies revealed that di-alkynyl substituent at the exocyclic position of DHPs possessed higher QSI activities than those of mono-alkynyl DHPs. Moreover, a hexyl-substituent at C3 of DHPs was beneficial to QSI activity while a phenyl substituent at C4 of DHPs was detrimental to QSI activity of analogues.https://www.mdpi.com/2079-6382/11/2/151quorum sensingalkyne synthesis<i>Pseudomonas aeruginosa</i>dihydropyrrolones |
| spellingShingle | Basmah Almohaywi Tsz Tin Yu George Iskander Shekh Sabir Mohan Bhadbhade David StC. Black Naresh Kumar Synthesis of Alkyne-Substituted Dihydropyrrolones as Bacterial Quorum-Sensing Inhibitors of <i>Pseudomonas aeruginosa</i> Antibiotics quorum sensing alkyne synthesis <i>Pseudomonas aeruginosa</i> dihydropyrrolones |
| title | Synthesis of Alkyne-Substituted Dihydropyrrolones as Bacterial Quorum-Sensing Inhibitors of <i>Pseudomonas aeruginosa</i> |
| title_full | Synthesis of Alkyne-Substituted Dihydropyrrolones as Bacterial Quorum-Sensing Inhibitors of <i>Pseudomonas aeruginosa</i> |
| title_fullStr | Synthesis of Alkyne-Substituted Dihydropyrrolones as Bacterial Quorum-Sensing Inhibitors of <i>Pseudomonas aeruginosa</i> |
| title_full_unstemmed | Synthesis of Alkyne-Substituted Dihydropyrrolones as Bacterial Quorum-Sensing Inhibitors of <i>Pseudomonas aeruginosa</i> |
| title_short | Synthesis of Alkyne-Substituted Dihydropyrrolones as Bacterial Quorum-Sensing Inhibitors of <i>Pseudomonas aeruginosa</i> |
| title_sort | synthesis of alkyne substituted dihydropyrrolones as bacterial quorum sensing inhibitors of i pseudomonas aeruginosa i |
| topic | quorum sensing alkyne synthesis <i>Pseudomonas aeruginosa</i> dihydropyrrolones |
| url | https://www.mdpi.com/2079-6382/11/2/151 |
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