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The complex lifecycle of the parasite and the emergence of drug\u2010resistant <jats:italic>Plasmodium falciparum<\/jats:italic> have hampered the efficacy of current anti\u2010malarial agents. To circumvent this situation, the present study attempts to demonstrate the blood\u2010stage anti\u2010plasmodial action of 26 hybrid compounds containing the three privileged bioactive scaffolds (sulfonamide, chalcone, and nitro group) with synergistic and multitarget action. These three parent scaffolds exhibit divergent activities, such as antibacterial, anti\u2010malarial, anti\u2010fungal, anti\u2010inflammatory, and anticancer. All the synthesised compounds were characterised using various spectroscopic techniques. The in vitro blood\u2010stage inhibitory activity of 26 hybrid compounds was evaluated against mixed\u2010stage culture (asynchronize) of human malarial parasite <jats:italic>P. falciparum, Pf<\/jats:italic> 3D7 at different concentrations ranging from 25.0\u2009\u00b5g\/mL to 0.78\u2009\u00b5g\/mL using SYBR 1 green assay, with IC<jats:sub>50<\/jats:sub> values determined after 48\u2009h of treatment based on the drug\u2010response curves. Two potent compounds (<jats:bold>11<\/jats:bold> and <jats:bold>10<\/jats:bold>), with 2\u2010Br and 2,6\u2010diCl substitutions, showed pronounced activity with IC<jats:sub>50<\/jats:sub> values of 5.4\u2009\u00b5g\/mL and 5.6\u2009\u00b5g\/mL, whereas others displayed varied activity with IC<jats:sub>50<\/jats:sub> values ranging from 7.0\u2009\u00b5g\/mL to 22.0\u2009\u00b5g\/mL. Both <jats:bold>11<\/jats:bold> and <jats:bold>10<\/jats:bold> showed greater susceptibility towards mature\u2010stage trophozoites than ring\u2010stage parasites. The hemolytic and in vitro cytotoxicity assays revealed that compounds <jats:bold>11<\/jats:bold> and <jats:bold>10<\/jats:bold> did not cause any toxic effects on host red blood cells (uninfected), human\u2010derived Mo7e cells, and murine\u2010derived BA\/F3 cells. The in vitro observations are consistent with the in silico studies using <jats:italic>P. falciparum<\/jats:italic>\u2010dihydrofolate reductase, where <jats:bold>11<\/jats:bold> and <jats:bold>10<\/jats:bold> showed a binding affinity of \u221210.4\u2009Kcal\/mol. This is the first report of the hybrid scaffold, 4\u2010nitrobenzenesulfonamide chalcones, demonstrating its potential as an anti\u2010plasmodial agent.<\/jats:p>","DOI":"10.1002\/ddr.22233","type":"journal-article","created":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T01:38:00Z","timestamp":1721353080000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Antiplasmodial action of 4\u2010nitrobenzenesulfonamide chalcones: Design, synthesis, characterisation, in vitro and in silico evaluation against blood stages of <i>Plasmodium falciparum<\/i> 3D7"],"prefix":"10.1002","volume":"85","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2710-2724","authenticated-orcid":false,"given":"Anju Agnes","family":"Tom","sequence":"first","affiliation":[{"name":"Department of Chemistry Pondicherry University Puducherry India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinoth","family":"Rajendran","sequence":"additional","affiliation":[{"name":"Department of Microbiology Pondicherry University Puducherry India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahammed Ameen","family":"Thottasseri","sequence":"additional","affiliation":[{"name":"Department of Chemistry Pondicherry University Puducherry India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koustav","family":"Goswami","sequence":"additional","affiliation":[{"name":"Department of Chemistry Pondicherry University Puducherry India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Souvik","family":"Roy","sequence":"additional","affiliation":[{"name":"Department of Chemistry Pondicherry University Puducherry India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gopika","family":"Gopan","sequence":"additional","affiliation":[{"name":"Department of Microbiology Pondicherry University Puducherry India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maheswaran","family":"Mani","sequence":"additional","affiliation":[{"name":"Department of Microbiology Pondicherry University Puducherry India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4426-983X","authenticated-orcid":false,"given":"Tharanikkarasu","family":"Kannan","sequence":"additional","affiliation":[{"name":"Department of Chemistry Pondicherry University Puducherry India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,7,18]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules25040904"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/534697"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/2164558"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2019.05.013"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ardp.201900350"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.15196"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.4155\/fmc-2019-0342"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1039\/c7nj03523c"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep42717"},{"key":"e_1_2_8_11_1","doi-asserted-by":"crossref","unstructured":"Dallakyan S. &Olson A. 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