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Towards novel antimicrobials / CHIARA COSTANZO
Swansea University Author: CHIARA COSTANZO
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DOI (Published version): 10.23889/SUthesis.65444
Abstract
The widespread use of antimicrobials has led to the development of resistance to most known active compounds. This has led to the necessity to discover new drugs or adopt new strategies in order to overcome resistance. Benzimidazole is a building block commonly found in pharmaceuticals. It is well k...
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Swansea, Wales, UK
2023
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Institution: | Swansea University |
Degree level: | Doctoral |
Degree name: | Ph.D |
Supervisor: | Loveridge, J. |
URI: | https://cronfa.swan.ac.uk/Record/cronfa65444 |
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2024-01-11T15:36:54Z |
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2024-11-25T14:16:05Z |
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v2 65444 2024-01-11 Towards novel antimicrobials 1248d4026380a8e298481190a9b56226 CHIARA COSTANZO CHIARA COSTANZO true false 2024-01-11 The widespread use of antimicrobials has led to the development of resistance to most known active compounds. This has led to the necessity to discover new drugs or adopt new strategies in order to overcome resistance. Benzimidazole is a building block commonly found in pharmaceuticals. It is well known for its antimicrobial, antiviral, anticancer and antiulcer properties as well as antihistaminic, anticoagulant and anti-inflammatory activity. In order to overcome bacterial resistance to β-lactam antibiotics, an in-silico screening of the designed benzimidazoles was undertaken leading to a library of compounds with good predicted binding affinity for lytic transglycosylases, a group of enzymes involved in the induction of β-lactamases. Strategies for extending the benzimidazole nucleus were developed, leading to the synthesis of 150 compounds. The synthetic strategies explored led to the discovery of a N1 / C2 competition with the recovery of two products in a one pot synthesis. This allowed formation of N1-alkylated and 2-phenyl analogues as well as 2-pyrrole and 2-thiophene derivatives. The consolidation of the most suitable synthetic method for extending the core in position number 2 furtherly led to bis-benzimidazoles and indole-benzimidazole hybrids. The benzimidazoles synthesized were screened against E. coli, S. aureus and P. aeruginosa, leading to the identification of hit compounds with antibacterial effect, one of them having a comparable activity to ampicillin. Furthermore, as benzimidazoles are well known for targeting tubulin, an attractive target for antiparasitic drugs, the effect of the benzimidazoles against S. mansoni was investigated in order to establish their activity against parasitic worms. A hit compound was selected for affecting both phenotype and motility in adult worms. Structure-activity relationship considerations have been proposed and the most promising core modifications leading to antibacterial or antiparasitic activity have been highlighted. Overall, this work has identified new antibacterial and antihelminthic hit compounds that can form the basis for future work to improve potency, confirm the compounds’ targets, and investigate other important medicinal chemistry considerations such as selectivity and ADME properties. E-Thesis Swansea, Wales, UK Antimicrobials, benzimidazoles, lytic transglycosylases, tubulin, Schistosoma mansoni, Eschericia coli, Staphylococcus aureus, Pseudomonas aeruginosa 12 12 2023 2023-12-12 10.23889/SUthesis.65444 Part of this thesis has been redacted to protect personal information COLLEGE NANME COLLEGE CODE Swansea University Loveridge, J. Doctoral Ph.D UKRI UKRI 2025-01-29T14:38:47.0011692 2024-01-11T15:24:21.3524478 Faculty of Science and Engineering School of Engineering and Applied Sciences - Chemistry CHIARA COSTANZO 1 65444__29434__76d69423e5d84f7d87c2e85e9a6dbd0d.pdf 2023_Costanzo_C.final.65444.pdf 2024-01-11T15:34:55.1910982 Output 20254726 application/pdf E-Thesis – open access true 2025-01-11T00:00:00.0000000 Distributed under the terms of a Creative Commons Attribution 4.0 License (CC BY 4.0). Copyright: The author, Chiara Costanzo, 2024. true eng https://creativecommons.org/licenses/by/4.0/ |
title |
Towards novel antimicrobials |
spellingShingle |
Towards novel antimicrobials CHIARA COSTANZO |
title_short |
Towards novel antimicrobials |
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Towards novel antimicrobials |
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Towards novel antimicrobials |
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Towards novel antimicrobials |
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Towards novel antimicrobials |
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1248d4026380a8e298481190a9b56226_***_CHIARA COSTANZO |
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CHIARA COSTANZO |
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CHIARA COSTANZO |
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The widespread use of antimicrobials has led to the development of resistance to most known active compounds. This has led to the necessity to discover new drugs or adopt new strategies in order to overcome resistance. Benzimidazole is a building block commonly found in pharmaceuticals. It is well known for its antimicrobial, antiviral, anticancer and antiulcer properties as well as antihistaminic, anticoagulant and anti-inflammatory activity. In order to overcome bacterial resistance to β-lactam antibiotics, an in-silico screening of the designed benzimidazoles was undertaken leading to a library of compounds with good predicted binding affinity for lytic transglycosylases, a group of enzymes involved in the induction of β-lactamases. Strategies for extending the benzimidazole nucleus were developed, leading to the synthesis of 150 compounds. The synthetic strategies explored led to the discovery of a N1 / C2 competition with the recovery of two products in a one pot synthesis. This allowed formation of N1-alkylated and 2-phenyl analogues as well as 2-pyrrole and 2-thiophene derivatives. The consolidation of the most suitable synthetic method for extending the core in position number 2 furtherly led to bis-benzimidazoles and indole-benzimidazole hybrids. The benzimidazoles synthesized were screened against E. coli, S. aureus and P. aeruginosa, leading to the identification of hit compounds with antibacterial effect, one of them having a comparable activity to ampicillin. Furthermore, as benzimidazoles are well known for targeting tubulin, an attractive target for antiparasitic drugs, the effect of the benzimidazoles against S. mansoni was investigated in order to establish their activity against parasitic worms. A hit compound was selected for affecting both phenotype and motility in adult worms. Structure-activity relationship considerations have been proposed and the most promising core modifications leading to antibacterial or antiparasitic activity have been highlighted. Overall, this work has identified new antibacterial and antihelminthic hit compounds that can form the basis for future work to improve potency, confirm the compounds’ targets, and investigate other important medicinal chemistry considerations such as selectivity and ADME properties. |
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2023-12-12T14:38:48Z |
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10.64435 |