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Synthesis structure-activity relationships and biological evaluation of optimised terminally alkylated (bis)urea and (bis)thiourea polyamine analogues as antiplasmodial agents
Dissertation (MSc)--University of Pretoria, 2017.
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| Format: | Thesis |
| Language: | English |
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University of Pretoria
2017
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| _version_ | 1867613527444815872 |
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| access_status_str | Open Access |
| author2 | Birkholtz, Lyn-Marie |
| author_browse | Birkholtz, Lyn-Marie |
| author_facet | Birkholtz, Lyn-Marie |
| collection | Thesis |
| dc_rights_str_mv | © 2017 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. |
| description | Dissertation (MSc)--University of Pretoria, 2017. |
| format | Thesis |
| id | oai:repository.up.ac.za:2263/63227 |
| institution | University of Pretoria (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:37:34.018Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UPSpace — University of Pretoria Institutional Repository |
| publishDate | 2017 |
| publishDateRange | 2017 |
| publishDateSort | 2017 |
| publisher | University of Pretoria |
| publisherStr | University of Pretoria |
| record_format | dspace |
| source_str | UPSpace — University of Pretoria Institutional Repository |
| spelling | oai:repository.up.ac.za:2263/63227 Synthesis structure-activity relationships and biological evaluation of optimised terminally alkylated (bis)urea and (bis)thiourea polyamine analogues as antiplasmodial agents Birkholtz, Lyn-Marie u10111442@tuks.co.za October, Natasha Besaans, Ethan Wade UCTD Dissertation (MSc)--University of Pretoria, 2017. The sustained control and elimination of malaria requires novel approaches to combat the emergence of drug resistance. Plasmodium falciparum causes the most lethal form of human malaria. Current therapeutics have shown decreased efficacy as a result of P. falciparum developing resistance to them. Consequently, novel antimalarial agents with new mechanisms of action are urgently needed to aid in the control and ultimate eradication of this disease and should display low resistance indices and high selectivity indices. Polyamines are involved in a variety of cellular functions including cell differentiation and proliferation and have been shown to be essential to malaria parasites in vitro. However, these analogues lacked drug-like properties, negating their use in malaria disease models in vivo. The objective of this study was to develop novel polyamine analogues based on a previous generation of compounds and to determine their antiplasmodial activity in vitro. Consequently, a novel series of (bis)urea and (bis)thiourea polyamine analogues were designed and synthesised with moderately high yields and purity. In silico evaluation of drug-likeness of these compounds indicated low oral bioavailability overall, although the predicted values were improved over the parent series. The antiplasmodial activity of the novel analogues indicated that halogenation generally decreases activity except for bromination, which did improve in vitro activity. Cheminformatics analysis enabled in-depth analysis of the structure-activity relationships (SAR) of this class of compounds, allowing structural features to be identified that are important for activity. Complementing the SAR with quantitative structure-activity relationships (QSAR) allowed the determination of a descriptor that weakly correlates with the analogues’ activities. The structural requirements for activity were found to be based on representations of the polyamine analogues molecular structures by means of circular atom neighbourhood’s. This work therefore contributed to the further development of the polyamine analogues as potential antimalarial drugs. National Research Foundation (NRF) South African Research Chair (SARChI) programme Biochemistry MSc Unrestricted 2017-11-20T11:58:43Z 2017-11-20T11:58:43Z 2017 2017 Dissertation Besaans, EW 2017, Synthesis structure-activity relationships and biological evaluation of optimised terminally alkylated (bis)urea and (bis)thiourea polyamine analogues as antiplasmodial agents, MSc Dissertation, University of Pretoria, Pretoria, viewed yymmdd <http://hdl.handle.net/2263/63227> S2017 http://hdl.handle.net/2263/63227 en © 2017 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. application/pdf University of Pretoria |
| spellingShingle | UCTD Synthesis structure-activity relationships and biological evaluation of optimised terminally alkylated (bis)urea and (bis)thiourea polyamine analogues as antiplasmodial agents |
| title | Synthesis structure-activity relationships and biological evaluation of optimised terminally alkylated (bis)urea and (bis)thiourea polyamine analogues as antiplasmodial agents |
| title_full | Synthesis structure-activity relationships and biological evaluation of optimised terminally alkylated (bis)urea and (bis)thiourea polyamine analogues as antiplasmodial agents |
| title_fullStr | Synthesis structure-activity relationships and biological evaluation of optimised terminally alkylated (bis)urea and (bis)thiourea polyamine analogues as antiplasmodial agents |
| title_full_unstemmed | Synthesis structure-activity relationships and biological evaluation of optimised terminally alkylated (bis)urea and (bis)thiourea polyamine analogues as antiplasmodial agents |
| title_short | Synthesis structure-activity relationships and biological evaluation of optimised terminally alkylated (bis)urea and (bis)thiourea polyamine analogues as antiplasmodial agents |
| title_sort | synthesis structure activity relationships and biological evaluation of optimised terminally alkylated bis urea and bis thiourea polyamine analogues as antiplasmodial agents |
| topic | UCTD |
| url | http://hdl.handle.net/2263/63227 |