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Although yields were low, it was possible to synthesise a small nine-membered library using the previously synthesised Boc-protected thiaplakortone A (2) as a scaffold for late-stage functionalisation. The new thiaplakortone A analogues (3\u201311) were generated using N-bromosuccinimide, N-iodosuccinimide or a Diversinate\u2122 reagent. The chemical structures of all new analogues were fully characterised by 1D\/2D NMR, UV, IR and MS data analyses. All compounds were evaluated for their antimalarial activity against Plasmodium falciparum 3D7 (drug-sensitive) and Dd2 (drug-resistant) strains. Incorporation of halogens at positions 2 and 7 of the thiaplakortone A scaffold was shown to reduce antimalarial activity compared to the natural product. Of the new compounds, the mono-brominated analogue (compound 5) displayed the best antimalarial activity with IC50 values of 0.559 and 0.058 \u03bcM against P. falciparum 3D7 and Dd2, respectively, with minimal toxicity against a human cell line (HEK293) observed at 80 \u03bcM. Of note, the majority of the halogenated compounds showed greater efficacy against the P. falciparum drug-resistant strain.<\/jats:p>","DOI":"10.3390\/md21050317","type":"journal-article","created":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T01:36:48Z","timestamp":1684805808000},"page":"317","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Synthesis and Antimalarial Evaluation of Halogenated Analogues of Thiaplakortone A"],"prefix":"10.3390","volume":"21","author":[{"given":"Folake A.","family":"Egbewande","sequence":"first","affiliation":[{"name":"Griffith Institute for Drug Discovery, School of Environment and Science, Griffith University, Nathan, QLD 4111, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett D.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Griffith Institute for Drug Discovery, School of Environment and Science, Griffith University, Nathan, QLD 4111, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Duffy","sequence":"additional","affiliation":[{"name":"Griffith Institute for Drug Discovery, School of Environment and Science, Griffith University, Nathan, QLD 4111, Australia"},{"name":"Discovery Biology, Centre for Cellular Phenomics, Griffith University, Nathan, QLD 4111, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4914-2299","authenticated-orcid":false,"given":"Vicky M.","family":"Avery","sequence":"additional","affiliation":[{"name":"Griffith Institute for Drug Discovery, School of Environment and Science, Griffith University, Nathan, QLD 4111, Australia"},{"name":"Discovery Biology, Centre for Cellular Phenomics, Griffith University, Nathan, QLD 4111, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4291-7573","authenticated-orcid":false,"given":"Rohan A.","family":"Davis","sequence":"additional","affiliation":[{"name":"Griffith Institute for Drug Discovery, School of Environment and Science, Griffith University, Nathan, QLD 4111, Australia"},{"name":"NatureBank, Griffith University, Nathan, QLD 4111, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2478\/acph-2023-0001","article-title":"Recent approaches in the drug research and development of novel antimalarial drugs with new targets","volume":"73","author":"Chinnappanna","year":"2023","journal-title":"Acta Pharm."},{"key":"ref_2","unstructured":"(2023, March 01). 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