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This approach holds great promise for the generation of potent drug leads in the quest for therapeutic chemotypes with the potential to overcome the development of clinical resistance. Herein, we present the <jats:italic>in\u2005vitro<\/jats:italic> antiplasmodial and antiproliferative investigation of ferrocenyl \u03b1\u2010aminocresol conjugates assembled by amalgamation of the organometallic ferrocene unit and an \u03b1\u2010aminocresol scaffold possessing antimalarial activity. The compounds pursued in the study exhibited higher toxicity towards the chemosensitive (3D7) and \u2010resistant (Dd2) strains of the <jats:italic>Plasmodium falciparum<\/jats:italic> parasite than to the human HCC70 triple\u2010negative breast cancer cell line. Indication of cross\u2010resistance was absent for the compounds evaluated against the multi\u2010resistant Dd2 strain. Structure\u2010activity analysis revealed that the phenolic hydroxy group and rotatable \u03c3 bond between the \u03b1\u2010carbon and NH group of the \u03b1\u2010amino\u2010<jats:italic>o<\/jats:italic>\u2010cresol skeleton are crucial for the biological activity of the compounds. Spectrophotometric techniques and <jats:italic>in silico<\/jats:italic> docking simulations performed on selected derivatives suggest that the compounds show a dual mode of action involving hemozoin inhibition and DNA interaction via minor\u2010groove binding. Lastly, compound <jats:bold>9\u2009a<\/jats:bold>, identified as a possible lead, exhibited preferential binding for the plasmodial DNA isolated from 3D7 <jats:italic>P. falciparum<\/jats:italic> trophozoites over the mammalian calf thymus DNA, thereby substantiating the enhanced antiplasmodial activity of the compounds. The presented research demonstrates the strategy of incorporating organometallic complexes into known biologically active organic scaffolds as a viable avenue to fashion novel multimodal compounds with potential to counter the development drug resistance.<\/jats:p>","DOI":"10.1002\/cbic.202000132","type":"journal-article","created":{"date-parts":[[2020,4,20]],"date-time":"2020-04-20T01:27:53Z","timestamp":1587346073000},"page":"2643-2658","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["The <i>in Vitro<\/i> Antiplasmodial and Antiproliferative Activity of New Ferrocene\u2010Based \u03b1\u2010Aminocresols Targeting Hemozoin Inhibition and DNA Interaction"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1608-6801","authenticated-orcid":false,"given":"Mziyanda","family":"Mbaba","sequence":"first","affiliation":[{"name":"Faculty of Science Department of Chemistry Rhodes University  Grahamstown 6140 South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3041-2861","authenticated-orcid":false,"given":"Laura M. 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