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The new derivatives were found to be active against both chloroquine (CQ)\u2010sensitive and CQ\u2010resistant strains of <jats:italic>P.\u2005falciparum<\/jats:italic>, with IC<jats:sub>50<\/jats:sub> values in the range of 7\u2013200\u2005n<jats:sc>M<\/jats:sc>; one compound showed in\u2005vivo activity.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/gif\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/mcontent.gif\"><jats:alt-text>magnified image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><jats:p><jats:italic>The prophylactic administration of amodiaquine (AQ), a 4\u2010aminoquinoline antimalarial drug, has been associated with side effects such as agranulocytosis and liver damage. The toxicity of this drug is mediated by amodiaquine quinone\u2010imine, an electrophilic metabolite. Replacement of the 4\u2032\u2010hydroxy function of AQ with various alkyl, aryl, or heteroaryl substituents would provide analogues that avoid metabolism to potentially toxic derivatives. Following a multistep procedure, 33 compounds containing hydrophobic groups at the 4\u2032\u2010position were synthesized using Csp<jats:sup>2<\/jats:sup>\u2013Csp<jats:sup>2<\/jats:sup> and Csp<jats:sup>2<\/jats:sup>\u2013Csp<jats:sup>3<\/jats:sup> Suzuki\u2013Miyaura cross\u2010coupling reactions as the key step. The new derivatives were found to be active against both chloroquine (CQ)\u2010sensitive and CQ\u2010resistant strains of<\/jats:italic> P.\u2005falciparum<jats:italic>, with IC<jats:sub>50<\/jats:sub> values in the range of 7\u2013200\u2005n<jats:sc>M<\/jats:sc>. Alkyl analogues are more efficient than aryl or heteroaryl derivatives. All compounds were also assessed for their cytotoxicity and ability to inhibit \u03b2\u2010hematin formation in\u2005vitro. A detailed investigation of the structure\u2013activity relationships for these new compounds was carried out; the 4\u2032\u2010methyl compound showed interesting in\u2005vivo antimalarial activity.<\/jats:italic><\/jats:p>","DOI":"10.1002\/cmdc.200800318","type":"journal-article","created":{"date-parts":[[2009,2,11]],"date-time":"2009-02-11T06:53:16Z","timestamp":1234335196000},"page":"549-561","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Replacement of the 4\u2032\u2010Hydroxy Group of Amodiaquine and Amopyroquine by Aromatic and Aliphatic Substituents: Synthesis and Antimalarial Activity"],"prefix":"10.1002","volume":"4","author":[{"given":"Emilia","family":"P\u0103unescu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Susplugas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuelle","family":"Boll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Varga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Mouray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ion","family":"Grosu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Grellier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Melnyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,4,9]]},"reference":[{"key":"e_1_2_7_1_2","doi-asserted-by":"publisher","DOI":"10.1002\/med.20062"},{"key":"e_1_2_7_2_2","unstructured":"\u00a0"},{"key":"e_1_2_7_3_2","unstructured":"WHO Expert Committee on Malaria Technical Report Series No.\u2005829 World Health Organization Geneva 2000;"},{"key":"e_1_2_7_4_2","unstructured":"World Malaria Report World Health Organization 2005 http:\/\/rbm.who.int\/wmr2005\/pdf\/WMReport_lr.pdf(accessed January 16 2009)."},{"key":"e_1_2_7_5_2","unstructured":"\u00a0"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/415686a"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1054\/drup.2001.0194"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1086\/322858"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1078167"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-2-31"},{"key":"e_1_2_7_11_2","unstructured":"\u00a0"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm960370r"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0163-7258(97)00084-3"},{"key":"e_1_2_7_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinorgbio.2005.04.013"},{"key":"e_1_2_7_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2003.08.009"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1021\/cg025550i"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(05)00077-8"},{"key":"e_1_2_7_18_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja01184a023"},{"key":"e_1_2_7_19_2","unstructured":"\u00a0"},{"key":"e_1_2_7_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(84)90410-0"},{"key":"e_1_2_7_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)65475-X"},{"key":"e_1_2_7_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(96)06217-4"},{"key":"e_1_2_7_23_2","unstructured":"\u00a0"},{"key":"e_1_2_7_24_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.1.5851.458"},{"key":"e_1_2_7_25_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.292.6522.721"},{"key":"e_1_2_7_26_2","unstructured":"\u00a0"},{"key":"e_1_2_7_27_2","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1016\/S0022-3565(24)36494-8","volume":"280","author":"Naisbitt D. 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