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Scaffolds with various substitutions were tested for antimalarial activity, and compounds <jats:bold>8\u2009g<\/jats:bold>, <jats:bold>8\u2009h<\/jats:bold>, and <jats:bold>15<\/jats:bold> exhibited EC50 values of \u223c0.018\u2005\u03bcM, \u223c0.069\u2005\u03bcM, and \u223c0.02\u2005\u03bcM, respectively. Structure\u2010based docking studies on falcipain\u20102\/3 proteases (PDB:2GHU and PDB:3BWK) revealed that compounds <jats:bold>8\u2009g<\/jats:bold>, <jats:bold>8\u2009h<\/jats:bold>, and <jats:bold>15<\/jats:bold> interact strongly with binding sites of falcipain\u20102\/3 in a substrate\u2010like manner. In silico ADME studies revealed that the molecules of interest showed no or minimal violations of drug\u2010likeness parameters. Further, phenotypic assays revealed that compound <jats:bold>8\u2009g<\/jats:bold> and its biotinylated version inhibit hemoglobin degradation in the parasite food vacuole. The identification of falcipain\u20102\/3 targeting potent inhibitors of the malaria parasite can serve as a starting point for the development of lead compounds as future antimalarial drug candidates.<\/jats:p>","DOI":"10.1002\/cmdc.202200709","type":"journal-article","created":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T00:57:00Z","timestamp":1675817820000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Histidinal\u2010Based Potent Antimalarial Agents"],"prefix":"10.1002","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0535-1964","authenticated-orcid":false,"given":"Chhuttan L.","family":"Meena","sequence":"first","affiliation":[{"name":"Organic Chemistry Division CSIR \u2013 National Chemical Laboratory  Dr. Homi Bhabha Road 411008 Pune India"},{"name":"Academy of Scientific and Innovative Research (AcSIR)  201002 Ghaziabad Uttar Pradesh India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tejashri","family":"Hingamire","sequence":"additional","affiliation":[{"name":"Biochemical Sciences Division CSIR \u2013 National Chemical Laboratory  Dr. Homi Bhabha Road 411008 Pune India"},{"name":"Academy of Scientific and Innovative Research (AcSIR)  201002 Ghaziabad Uttar Pradesh India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanya","family":"Gupta","sequence":"additional","affiliation":[{"name":"Biochemical Sciences Division CSIR \u2013 National Chemical Laboratory  Dr. Homi Bhabha Road 411008 Pune India"},{"name":"Academy of Scientific and Innovative Research (AcSIR)  201002 Ghaziabad Uttar Pradesh India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bhagyashree","family":"Deshmukh","sequence":"additional","affiliation":[{"name":"Indian Institute of Science Education and Research (IISER)  Dr. Homi Bhabha Road 411008 Pune India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5714-0587","authenticated-orcid":false,"given":"Krishanpal","family":"Karmodiya","sequence":"additional","affiliation":[{"name":"Indian Institute of Science Education and Research (IISER)  Dr. Homi Bhabha Road 411008 Pune India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8016-1178","authenticated-orcid":false,"given":"Rakesh","family":"Joshi","sequence":"additional","affiliation":[{"name":"Biochemical Sciences Division CSIR \u2013 National Chemical Laboratory  Dr. Homi Bhabha Road 411008 Pune India"},{"name":"Academy of Scientific and Innovative Research (AcSIR)  201002 Ghaziabad Uttar Pradesh India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3341-4846","authenticated-orcid":false,"given":"Dhanasekaran","family":"Shanmugam","sequence":"additional","affiliation":[{"name":"Biochemical Sciences Division CSIR \u2013 National Chemical Laboratory  Dr. Homi Bhabha Road 411008 Pune India"},{"name":"Academy of Scientific and Innovative Research (AcSIR)  201002 Ghaziabad Uttar Pradesh India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7764-7329","authenticated-orcid":false,"given":"Gangadhar J.","family":"Sanjayan","sequence":"additional","affiliation":[{"name":"Organic Chemistry Division CSIR \u2013 National Chemical Laboratory  Dr. Homi Bhabha Road 411008 Pune India"},{"name":"Academy of Scientific and Innovative Research (AcSIR)  201002 Ghaziabad Uttar Pradesh India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,2,28]]},"reference":[{"key":"e_1_2_8_1_1","unstructured":"https:\/\/www.who.int\/teams\/global-malaria-programme\/reports\/world-malaria-report-2022."},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2458-9-259"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3073"},{"key":"e_1_2_8_4_1","unstructured":"The Editors of Encyclopaedia. \u201cchloroquine\u201d Encyclopedia Britannica 14 Apr.2020 https:\/\/www.britannica.com\/science\/chloroquine. 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