{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T04:37:22Z","timestamp":1783917442643,"version":"3.55.0"},"reference-count":72,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2021,7,8]],"date-time":"2021-07-08T00:00:00Z","timestamp":1625702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>An efficient synthesis of rac-6-desmethyl-5\u03b2\u2013hydroxy-d-secoartemisinin 2, a tricyclic analog of R-(+)-artemisinin 1, was accomplished and the racemate was resolved into the (+)-2b and (\u2212)-2a enantiomers via their Mosher Ester diastereomers. Antimalarial activity resided with only the artemisinin-like enantiomer R-(\u2212)-2a. Several new compounds 9\u201316, 19a, 19b, 22 and 29 were synthesized from rac-2 but the C-5 secondary hydroxyl group was surprisingly unreactive. For example, the formation of carbamates and Mitsunobu reactions were unsuccessful. In order to assess the unusual reactivity of 2, a single crystal X-ray crystallographic analysis revealed a close intramolecular hydrogen bond from the C-5 alcohol to the oxepane ether oxygen (O-11). All products were tested in vitro against the W-2 and D-6 strains of Plasmodium falciparum. Several of the analogs had moderate activity in comparison to the natural product 1. Iron (II) bromide-promoted rearrangement of 2 gave, in 50% yield, the ring-contracted tetrahydrofuran 22, while the 5-ketone 15 provided a monocyclic methyl ketone 29 (50%). Neither 22 nor 29 possessed in vitro antimalarial activity. These results have implications in regard to the antimalarial mechanism of action of artemisinin.<\/jats:p>","DOI":"10.3390\/molecules26144163","type":"journal-article","created":{"date-parts":[[2021,7,8]],"date-time":"2021-07-08T21:05:54Z","timestamp":1625778354000},"page":"4163","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Structure\u2013Activity Relationships of the Antimalarial Agent Artemisinin 10. Synthesis and Antimalarial Activity of Enantiomers of rac-5\u03b2-Hydroxy-d-Secoartemisinin and Analogs: Implications Regarding the Mechanism of Action"],"prefix":"10.3390","volume":"26","author":[{"given":"Mohamed","family":"Jahan","sequence":"first","affiliation":[{"name":"Department of BioMolecular Sciences, Division Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, MS 38677, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5064-2381","authenticated-orcid":false,"given":"Francisco","family":"Leon","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC 29208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank R.","family":"Fronczek","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2394-021X","authenticated-orcid":false,"given":"Khaled M.","family":"Elokely","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Tanta University, Tanta 31527, Egypt"},{"name":"Department of Chemistry, Institute for Computational Molecular Science, Temple University, Philadelphia, PA 19122, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Rimoldi","sequence":"additional","affiliation":[{"name":"Department of BioMolecular Sciences, Division Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, MS 38677, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shabana I.","family":"Khan","sequence":"additional","affiliation":[{"name":"National Center for Natural Product Research, University of Mississippi, University, MS 38677, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2177-7535","authenticated-orcid":false,"given":"Mitchell A.","family":"Avery","sequence":"additional","affiliation":[{"name":"Department of BioMolecular Sciences, Division Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, MS 38677, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Avery, M.A., Weldon, D., and Muraleedharan, K. 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