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There is widespread clinical resistance to the most commonly prescribed antimalarial drugs. To address this issue, we synthesized a range of 4\u2032\u2010pyrrolidinodiazenyl chalcones using a covalent bitherapy approach to study their potential antimalarial properties. We examined the structure\u2013activity relationships of these compounds, which could explain their antimalarial activities. The in\u00a0vitro blood stage antimalarial activity of the compounds was evaluated against the mixed\u2010blood stage culture (ring, trophozoites and schizonts) of\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    3D7, and the 50% inhibitory concentrations (IC\n                    <jats:sub>50<\/jats:sub>\n                    s) ranged from 3.3 to 22.2\u2009\u03bcg\/mL after 48\u2009h of exposure. Compounds\n                    <jats:bold>11<\/jats:bold>\n                    ,\n                    <jats:bold>19<\/jats:bold>\n                    , and\n                    <jats:bold>22<\/jats:bold>\n                    displayed pronounced IC\n                    <jats:sub>50<\/jats:sub>\n                    values of 7.6\u2009\u03bcg\/mL, 6.4\u2009\u03bcg\/mL, and 3.3\u2009\u03bcg\/mL, respectively. The in\u00a0vitro cytotoxicity of the active compounds was evaluated on human\u2010derived Mo7e cells and murine\u2010derived BA\/F3 cells. Compounds\n                    <jats:bold>11<\/jats:bold>\n                    and\n                    <jats:bold>19<\/jats:bold>\n                    were found to be noncytotoxic (&gt;\u200940\u2009\u03bcg\/mL), whereas compound\n                    <jats:bold>22<\/jats:bold>\n                    displayed cytotoxicity at higher concentrations. Moreover, these compounds exerted negligible hemolytic effects on human RBCs at their active concentrations. Molecular docking of these compounds revealed good hydrophobic and hydrogen bonding interactions with the binding sites of\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    \u2010dihydrofolate reductase, providing a rationale for their antimalarial activity, which is consistent with the in\u00a0vitro results.\n                  <\/jats:p>","DOI":"10.1111\/cbdd.70081","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T06:14:43Z","timestamp":1741760083000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Targeting Blood\u2010Stage Malaria: Design, Synthesis, Characterization, In\u00a0Vitro, and\n                    <i>In Silico<\/i>\n                    Evaluation of Pyrrolidinodiazenyl Chalcones"],"prefix":"10.1111","volume":"105","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0516-1770","authenticated-orcid":false,"given":"Ahammed Ameen","family":"Thottasseri","sequence":"first","affiliation":[{"name":"Department of Chemistry Pondicherry University  Kalapet Puducherry India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinoth","family":"Rajendran","sequence":"additional","affiliation":[{"name":"Department of Microbiology Pondicherry University  Kalapet Puducherry India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepthi","family":"Ramesh","sequence":"additional","affiliation":[{"name":"Department of Chemistry Pondicherry University  Kalapet Puducherry India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2710-2724","authenticated-orcid":false,"given":"Anju Agnes","family":"Tom","sequence":"additional","affiliation":[{"name":"Department of Chemistry Pondicherry University  Kalapet Puducherry India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roshiny 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