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This problem is compounded by the decreased efficacy of artemisinin combination therapies. Therefore, the development and optimisation of novel antimalarial chemotypes is critical. In this study, we describe our strategic approach to optimise a class of previously reported antimalarials, resulting in the discovery of 1\u2010(5\u2010chloro\u20101<jats:italic>H<\/jats:italic>\u2010indol\u20103\u2010yl)\u20102\u2010[(4\u2010cyanophenyl)thio]ethanone (<jats:bold>13<\/jats:bold>) and 1\u2010(5\u2010chloro\u20101<jats:italic>H<\/jats:italic>\u2010indol\u20103\u2010yl)\u20102\u2010[(4\u2010nitrophenyl)thio]ethanone (<jats:bold>14<\/jats:bold>), whose activity was equipotent to that of chloroquine against the <jats:italic>P.\u2005falciparum<\/jats:italic> 3D7 strain. Furthermore, these compounds were found to be nontoxic to HeLa cells as well as being non\u2010haemolytic to uninfected red blood cells. Intriguingly, several of our most promising compounds were found to be less active against the isogenic NF54 strain, highlighting possible issues with long\u2010term dependability of malarial strains. Finally compound <jats:bold>14<\/jats:bold> displayed similar activity against both the NF54 and K1 strains, suggesting that it inhibits a pathway that is uncompromised by K1 resistance.<\/jats:p>","DOI":"10.1002\/cmdc.201800235","type":"journal-article","created":{"date-parts":[[2018,5,14]],"date-time":"2018-05-14T02:29:16Z","timestamp":1526264956000},"page":"1353-1362","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Expanding the SAR of Nontoxic Antiplasmodial Indolyl\u20103\u2010ethanone Ethers and Thioethers"],"prefix":"10.1002","volume":"13","author":[{"given":"Mayibongwe J.","family":"Lunga","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy Rhodes University  Grahamstown 6140 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruramai L.","family":"Chisango","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy Rhodes University  Grahamstown 6140 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carli","family":"Weyers","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy Rhodes University  Grahamstown 6140 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Isaacs","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Microbiology Rhodes University  Grahamstown 6140 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dale","family":"Taylor","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine University of Cape Town  Groote Schuur Hospital, Observatory 7925 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3615-6651","authenticated-orcid":false,"given":"Adrienne L.","family":"Edkins","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Microbiology Rhodes University  Grahamstown 6140 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0725-5738","authenticated-orcid":false,"given":"Setshaba D.","family":"Khanye","sequence":"additional","affiliation":[{"name":"Department of Chemistry Rhodes University  Grahamstown 6140 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4409-1955","authenticated-orcid":false,"given":"Heinrich C.","family":"Hoppe","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Microbiology Rhodes University  Grahamstown 6140 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4043-7106","authenticated-orcid":false,"given":"Clinton G. 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