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Its development is hampered due to limited bioavailability, so in this study, we synthesised analogues of ajoene to probe the significance of the ajoene vinyl disulfide\/sulfoxide core with respect to cytotoxicity and blood stability. Polar side groups were also incorporated to improve aqueous solubility. It was found that derivatives containing a vinyl disulfide functional group (<jats:bold>4<\/jats:bold>\u2013<jats:bold>7<\/jats:bold>, as in ajoene), were more cytotoxic compared to analogues in which the double bond was removed, although the latter showed superior blood stability. It was also found that the allyl\u2010<jats:italic>S<\/jats:italic> sulfur of the disulfide was more electrophilic to <jats:italic>S<\/jats:italic>\u2010thiolysis based on the global electrophilicity index (<jats:italic>\u03c9<\/jats:italic>) and the condensed electrophilic Fukui function \n. <jats:italic>S<\/jats:italic>\u2010Thiolysis was found to be exergonic for the vinyl disulfides based on entropy and enthalpy computations with a deprotonated thiolate. Derivatisation to the dihydro (<jats:bold>10<\/jats:bold>, <jats:bold>12<\/jats:bold>) and deoxydihydroajoenes (<jats:bold>9<\/jats:bold>, <jats:bold>11<\/jats:bold>) produced analogues that were slightly less potent but with greatly improved blood stability. Taken together, the deoxydihydroajoenes present themselves as good candidates for further therapeutic development.<\/jats:p>","DOI":"10.1002\/cmdc.202400087","type":"journal-article","created":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T02:45:07Z","timestamp":1711507507000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Finding the Ajoene Sweet\u2010Spot: Structure\u2010Activity Relations that Govern its Blood Stability and Cancer Cytotoxicity"],"prefix":"10.1002","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4930-5855","authenticated-orcid":false,"given":"Daniel A.","family":"Kusza","sequence":"first","affiliation":[{"name":"Department of Chemistry University of Cape Town, Rondebosch  Cape Town 7701 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3993-1198","authenticated-orcid":false,"given":"Gerhard A.","family":"Venter","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Cape Town, Rondebosch  Cape Town 7701 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandla","family":"Mabunda","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Cape Town, Rondebosch  Cape Town 7701 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1797-3226","authenticated-orcid":false,"given":"James","family":"Biwi","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Cape Town, Rondebosch  Cape Town 7701 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2892-653X","authenticated-orcid":false,"given":"Suman K.","family":"Samanta","sequence":"additional","affiliation":[{"name":"Faculty of Science Assam down town University  Sankar Madhab Path, Gandi Nagar, Panikhaiti, Guwahati 781026 Assam India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7759-3332","authenticated-orcid":false,"given":"Johan D.","family":"Klinck","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Polymer Science Stellenbosch University  Matieland 7600 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3733-144X","authenticated-orcid":false,"given":"Shivendra V.","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Chemical Biology University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania USA"},{"name":"University of Pittsburgh School of Medicine UPMC Hillman Cancer Centre  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8775-083X","authenticated-orcid":false,"given":"Roger","family":"Hunter","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Cape Town, Rondebosch  Cape Town 7701 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7594-5269","authenticated-orcid":false,"given":"Catherine H.","family":"Kaschula","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Polymer Science Stellenbosch University  Matieland 7600 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,5,14]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"crossref","unstructured":"E. 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