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The recent development of\n                      <jats:bold>ADC-028<\/jats:bold>\n                      , a 4-aminoquinoline antimalarial with excellent activity and pharmacokinetic properties, prompted the investigation of bisquinoline analogs featuring similar structural motifs. Here, we describe a structure-activity relationship study that guided the optimization of compounds with key features, including the 4-anilinoquinoline core and diverse bridging linkers. Several analogs exhibited potent\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      activity (IC\n                      <jats:sub>50<\/jats:sub>\n                      &lt; 20 nM) against both drug-sensitive and multidrug-resistant\n                      <jats:italic toggle=\"yes\">P. falciparum<\/jats:italic>\n                      strains, while maintaining favorable cytotoxicity profiles. Among them,\n                      <jats:bold>25<\/jats:bold>\n                      demonstrated improved intrinsic metabolic stability (t\n                      <jats:sub>1\/2<\/jats:sub>\n                      = 121 min) and potent\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      efficacy (ED\n                      <jats:sub>50<\/jats:sub>\n                      = 0.32 mg\/kg\/day), achieving complete curative protection at a reduced dose compared to ADC-028. While\n                      <jats:bold>25<\/jats:bold>\n                      showed moderately reduced oral bioavailability (F = 43%) and a shorter half-life (T\n                      <jats:sub>1\/2<\/jats:sub>\n                      = 27.2 h) relative to ADC-028, its enhanced\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      efficacy underscores its therapeutic potential. This work highlights a promising path forward in developing antimalarials that retain the efficacy of legacy compounds while overcoming modern resistance mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.01300-25","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T16:02:56Z","timestamp":1772467376000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Designing novel bisquinoline antimalarials from historical 4-aminoquinolines to combat drug-resistant malaria"],"prefix":"10.1128","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6764-3893","authenticated-orcid":true,"given":"Mason J.","family":"Handford","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/009avj582","id-type":"ROR","asserted-by":"publisher"}],"name":"Chemical Physiology and Biochemistry Department, Oregon Health & Science University","place":["Portland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuexin","family":"Li","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dv7fn73","id-type":"ROR","asserted-by":"publisher"}],"name":"Experimental Chemotherapy Lab, Portland VA Research Foundation","place":["Portland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry","family":"Riscoe","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dv7fn73","id-type":"ROR","asserted-by":"publisher"}],"name":"Experimental Chemotherapy Lab, Portland VA Research Foundation","place":["Portland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Zhang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dv7fn73","id-type":"ROR","asserted-by":"publisher"}],"name":"Experimental Chemotherapy Lab, Portland VA Research Foundation","place":["Portland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane X.","family":"Kelly","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dv7fn73","id-type":"ROR","asserted-by":"publisher"}],"name":"Experimental Chemotherapy Lab, Portland VA Research Foundation","place":["Portland, USA"]},{"id":[{"id":"https:\/\/ror.org\/00yn2fy02","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemistry, Portland State University","place":["Portland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1343-5279","authenticated-orcid":true,"given":"Michael K.","family":"Riscoe","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dv7fn73","id-type":"ROR","asserted-by":"publisher"}],"name":"Experimental Chemotherapy Lab, Portland VA Research Foundation","place":["Portland, USA"]},{"id":[{"id":"https:\/\/ror.org\/009avj582","id-type":"ROR","asserted-by":"publisher"}],"name":"Molecular Microbiology and Immunology Department, Oregon Health & Science University","place":["Portland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","unstructured":"WHO. 2024. World Malaria Report 2024. 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Resistance of Plasmodium berghei to chloroquine and 4-aminoquinolines. Ann Soc Belges Med Trop Parasitol Mycol 45:455\u2013458.","journal-title":"Ann Soc Belges Med Trop Parasitol Mycol"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.3390\/molecules25092251"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm8012618"},{"key":"e_1_3_4_15_2","first-page":"225","volume-title":"Handbook of experimental pharmacology","author":"Ager AL","year":"1984","unstructured":"Ager AL. 1984. Rodent malaria models. In antimalarial drugs I: biological background, experimental methods, and drug resistance, p 225\u2013264. In Peters W, Richards WHG (ed), Handbook of experimental pharmacology. 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