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Towards novel antimicrobials / CHIARA COSTANZO

Swansea University Author: CHIARA COSTANZO

  • E-Thesis – open access under embargo until: 11th January 2025

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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Published: Swansea, Wales, UK 2023
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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first_indexed 2024-01-11T15:36:54Z
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spelling 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 2024-04-12T11:20:27.6635236 2024-01-11T15:24:21.3524478 Faculty of Science and Engineering School of Engineering and Applied Sciences - Chemistry CHIARA COSTANZO 1 Under embargo Under embargo 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
title_full Towards novel antimicrobials
title_fullStr Towards novel antimicrobials
title_full_unstemmed Towards novel antimicrobials
title_sort Towards novel antimicrobials
author_id_str_mv 1248d4026380a8e298481190a9b56226
author_id_fullname_str_mv 1248d4026380a8e298481190a9b56226_***_CHIARA COSTANZO
author CHIARA COSTANZO
author2 CHIARA COSTANZO
format E-Thesis
publishDate 2023
institution Swansea University
doi_str_mv 10.23889/SUthesis.65444
college_str Faculty of Science and Engineering
hierarchytype
hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Engineering and Applied Sciences - Chemistry{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Chemistry
document_store_str 0
active_str 0
description 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.
published_date 2023-12-12T11:20:24Z
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score 11.014291

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