{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T09:26:26Z","timestamp":1787045186165,"version":"build-2736575974"},"reference-count":34,"publisher":"American Chemical Society (ACS)","issue":"7","license":[{"start":{"date-parts":[[2020,5,6]],"date-time":"2020-05-06T00:00:00Z","timestamp":1588723200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2020,5,6]],"date-time":"2020-05-06T00:00:00Z","timestamp":1588723200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2020,5,6]],"date-time":"2020-05-06T00:00:00Z","timestamp":1588723200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["1016357"],"award-info":[{"award-number":["1016357"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006312","name":"South African Agency for Science and Technology Advancement","doi-asserted-by":"publisher","award":["112089"],"award-info":[{"award-number":["112089"]}],"id":[{"id":"10.13039\/501100006312","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006312","name":"South African Agency for Science and Technology Advancement","doi-asserted-by":"publisher","award":["93430"],"award-info":[{"award-number":["93430"]}],"id":[{"id":"10.13039\/501100006312","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006312","name":"South African Agency for Science and Technology Advancement","doi-asserted-by":"publisher","award":["93732"],"award-info":[{"award-number":["93732"]}],"id":[{"id":"10.13039\/501100006312","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004477","name":"Universiteit Stellenbosch","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004477","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Pantothenamides (PanAms) are potent antiplasmodials with low human toxicity currently being investigated as antimalarials with a novel mode of action. These structural analogues of pantothenate, the vitamin precursor of the essential cofactor coenzyme A, are susceptible to degradation by pantetheinase enzymes present in serum. We previously discovered that \u03b1-methylation of the \u03b2-alanine moiety of PanAms increases their stability in serum and identified N-phenethyl-\u03b1-methyl-pantothenamide as a pantetheinase-resistant PanAm with potent, on-target, and selective antiplasmodial activity. In this study, we performed structure\u2013activity relationship investigations to establish whether stability and potency can be improved further through alternative modification of the scissile amide bond and through substitution\/modification of the phenyl ring. Additionally, for the first time, the importance of the stereochemistry of the \u03b1-methyl group was evaluated in terms of stability versus potency. Our results demonstrate that \u03b1-methylation remains the superior choice for amide modification, and that while monofluoro-substitution of the phenyl ring (that often improves ADME properties) was tolerated, N-phenethyl-\u03b1-methyl-pantothenamide remains the most potent analogue. We show that the 2S,2\u2032R-diastereomer is far more potent than the 2R,2\u2032R-diastereomer and that this cannot be attributed to preferential metabolic activation by pantothenate kinase, the first enzyme of the coenzyme A biosynthesis pathway. Unexpectedly, the more potent 2S,2\u2032R-diastereomer is also more prone to pantetheinase-mediated degradation. Finally, the results of in vitro studies to assess permeability and metabolic stability of the 2S,2\u2032R-diastereomer suggested species-dependent degradation via amide hydrolysis. Our study provides important information for the continued development of PanAm-based antimalarials.<\/jats:p>","DOI":"10.1021\/acsinfecdis.0c00075","type":"journal-article","created":{"date-parts":[[2020,5,6]],"date-time":"2020-05-06T20:08:56Z","timestamp":1588795736000},"page":"1844-1854","source":"Crossref","is-referenced-by-count":22,"title":["Toward a Stable and Potent Coenzyme A\u2011Targeting\nAntiplasmodial Agent: Structure\u2013Activity\nRelationship Studies of\n                    <i>N<\/i>\n                    \u2011Phenethyl-\u03b1-methyl-pantothenamide"],"prefix":"10.1021","volume":"6","author":[{"given":"Christina","family":"Spry","sequence":"first","affiliation":[{"name":"The Australian National University , , , ,","place":["Canberra, Australian Capital Territory, Australia, 2601"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leanne","family":"Barnard","sequence":"additional","affiliation":[{"name":"Stellenbosch University , , ,","place":["Stellenbosch, South Africa, 7600"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miche\u0301lle","family":"Kok","sequence":"additional","affiliation":[{"name":"Stellenbosch University , , ,","place":["Stellenbosch, South Africa, 7600"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew K.","family":"Powell","sequence":"additional","affiliation":[{"name":"Monash Institute of Pharmaceutical Sciences , , 381 Royal Parade , , ,","place":["Parkville, Victoria, Australia, 3052"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darvina","family":"Mahesh","sequence":"additional","affiliation":[{"name":"The Australian National University , , , ,","place":["Canberra, Australian Capital Territory, Australia, 2601"]},{"name":"The Australian National University , , , ,","place":["Canberra, Australian Capital Territory, Australia, 2601"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erick T.","family":"Tjhin","sequence":"additional","affiliation":[{"name":"The Australian National University , , , ,","place":["Canberra, Australian Capital Territory, Australia, 2601"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3345-8440","authenticated-orcid":true,"given":"Kevin J.","family":"Saliba","sequence":"additional","affiliation":[{"name":"The Australian National University , , , ,","place":["Canberra, Australian Capital Territory, Australia, 2601"]},{"name":"The Australian National University , , , ,","place":["Canberra, Australian Capital Territory, Australia, 2601"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9898-8226","authenticated-orcid":true,"given":"Erick","family":"Strauss","sequence":"additional","affiliation":[{"name":"Stellenbosch University , , ,","place":["Stellenbosch, South Africa, 7600"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6233-3498","authenticated-orcid":true,"given":"Marianne","family":"de Villiers","sequence":"additional","affiliation":[{"name":"Stellenbosch University , , ,","place":["Stellenbosch, South Africa, 7600"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,5,6]]},"reference":[{"issue":"4","key":"2026081722185784800_cit1","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1042\/BST20140158","article-title":"Exploiting the coenzyme A biosynthesis pathway for the identification\nof new antimalarial agents: the case for pantothenamides","volume":"42","author":"Saliba","year":"2014","journal-title":"Biochem. Soc. Trans."},{"issue":"4","key":"2026081722185784800_cit2","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.1042\/BST20140131","article-title":"Recent advances in targeting coenzyme A biosynthesis\nand utilization for antimicrobial drug development","volume":"42","author":"Moolman","year":"2014","journal-title":"Biochem. Soc. Trans."},{"issue":"2","key":"2026081722185784800_cit3","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0054974","article-title":"Pantothenamides\nare potent, on-target inhibitors of Plasmodium falciparum growth when serum pantetheinase is inactivated","volume":"8","author":"Spry","year":"2013","journal-title":"PLoS One"},{"issue":"8","key":"2026081722185784800_cit4","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1021\/ml400180d","article-title":"Structural modification of pantothenamides\ncounteracts degradation by pantetheinase and improves antiplasmodial\nactivity","volume":"4","author":"De Villiers","year":"2013","journal-title":"ACS Med. Chem. Lett."},{"key":"2026081722185784800_cit5","doi-asserted-by":"crossref","unstructured":"World\nHealth Organization\n          . (2019) World Malaria Report 2019, pp 1\u2013232, WHO.","DOI":"10.1007\/978-1-4614-6439-6_76-2"},{"issue":"3","key":"2026081722185784800_cit6","doi-asserted-by":"publisher","first-page":"200","DOI":"10.2174\/187152610791163390","article-title":"Pantothenate utilization\nby Plasmodium as a target for antimalarial chemotherapy","volume":"10","author":"Spry","year":"2010","journal-title":"Infect. Disord.: Drug Targets"},{"key":"2026081722185784800_cit7","first-page":"351","article-title":"Coenzyme A Biosynthesis and Enzymology","volume-title":"Comprehensive Natural Products II Chemistry and Biology","author":"Strauss","year":"2010"},{"issue":"3","key":"2026081722185784800_cit8","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1021\/cb3006424","article-title":"Discovery\nof small molecule vanin inhibitors: new tools to study metabolism\nand disease","volume":"8","author":"Jansen","year":"2013","journal-title":"ACS Chem. Biol."},{"issue":"12","key":"2026081722185784800_cit9","doi-asserted-by":"publisher","first-page":"7146","DOI":"10.1128\/AAC.01436-16","article-title":"Triazole substitution of a labile\namide bond stabilizes pantothenamides and improves their antiplasmodial\npotency","volume":"60","author":"Howieson","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026081722185784800_cit10","unstructured":"Hermkens, P. H. H., Schalkwijk, J., Jansen, P. A. M., and Botman, P. Pantothenamide analogues. Patent WO2016072854 A2, 2016."},{"issue":"510","key":"2026081722185784800_cit11","doi-asserted-by":"publisher","first-page":"eaas9917","DOI":"10.1126\/scitranslmed.aas9917","article-title":"Antimalarial\npantothenamide metabolites target acetyl-coenzyme A biosynthesis in Plasmodium falciparum","volume":"11","author":"Schalkwijk","year":"2019","journal-title":"Sci. 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