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DATP <jats:bold>19 (<\/jats:bold>3,5\u2010bis(4\u2010hydroxy\u20103,5\u2010dimethoxybenzylidene)tetrahydro\u20102<jats:italic>H<\/jats:italic>\u2010pyran\u20104(3<jats:italic>H<\/jats:italic>)\u2010one) was found to be the most potent (IC<jats:sub>50<\/jats:sub> 1.07\u2005\u03bcM) against <jats:italic>Pf<\/jats:italic>MRA\u20101240, whereas <jats:bold>21<\/jats:bold> (3,5\u2010bis(3,4,5\u2010trimethoxybenzylidene)tetrahydro\u20102<jats:italic>H<\/jats:italic>\u2010pyran\u20104(3<jats:italic>H<\/jats:italic>)\u2010one) showed IC<jats:sub>50<\/jats:sub> values of 1.72 and 1.44\u2005\u03bcM against <jats:italic>Pf<\/jats:italic>3D7 and <jats:italic>Pf<\/jats:italic>INDO, respectively. Resistance indices (RI) as low as 0.2 to 0.5 for <jats:bold>10<\/jats:bold> (3,5\u2010bis(4\u2010nitrobenzylidene)tetrahydro\u20102<jats:italic>H<\/jats:italic>\u2010pyran\u20104(3<jats:italic>H<\/jats:italic>)\u2010one) and <jats:bold>20<\/jats:bold> (3,5\u2010bis(3\u2010nitrobenzylidene)tetrahydro\u20102<jats:italic>H<\/jats:italic>\u2010pyran\u20104(3<jats:italic>H<\/jats:italic>)\u2010one), and &lt;1 for most other DATPs reveals their greater potency against resistant strains than the sensitive one. The single\u2010crystal XRD data for DATP <jats:bold>21<\/jats:bold> are reported. <jats:italic>In silico<\/jats:italic> support was obtained through docking studies. Killing all three strains within 4\u20138\u2005h, these DATPs showed rapid kill kinetics toward the trophozoite stage. Furthermore, DATP <jats:bold>18<\/jats:bold> (3,5\u2010bis(quinolin\u20104\u2010ylmethylene)tetrahydro\u20102<jats:italic>H<\/jats:italic>\u2010pyran\u20104(3<jats:italic>H<\/jats:italic>)\u2010one) inhibited <jats:italic>Pf<\/jats:italic>Pdx1 enzyme activity with IC<jats:sub>50<\/jats:sub> 20.34\u2005\u03bcM, which is about twofold lower than that (IC<jats:sub>50<\/jats:sub> 43\u2005\u03bcM) for an already known inhibitor 4PEHz. At an oral dose of 300\u2005mg\/kg body weight, DATPs <jats:bold>19<\/jats:bold> and <jats:bold>21<\/jats:bold> were found to be nontoxic to mice, and at 100\u2005mg\/kg body weight, DATP <jats:bold>19<\/jats:bold> was found to suppress parasitaemia, which led to an increase in median survival time by three days relative to untreated control mice in a malaria curative study.<\/jats:p>","DOI":"10.1002\/cmdc.202200411","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T11:38:12Z","timestamp":1666006692000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Antiplasmodial and Antimalarial Activity of 3,5\u2010Diarylidenetetrahydro\u20102<i>H<\/i>\u2010pyran\u20104(3<i>H<\/i>)\u2010ones via Inhibition of <i>Plasmodium falciparum<\/i> Pyridoxal Synthase"],"prefix":"10.1002","volume":"18","author":[{"given":"Hariharan","family":"Moorthy","sequence":"first","affiliation":[{"name":"Department of Chemistry Sri Sathya Sai Institute of Higher Learning  Puttaparthi Andhra Pradesh 515134 India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mamta","family":"Yadav","sequence":"additional","affiliation":[{"name":"Malaria Drug Discovery Laboratory International Centre for Genetic Engineering and Biotechnology (ICGEB)  New Delhi 110067 India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6014-7990","authenticated-orcid":false,"given":"Nitesh","family":"Tamang","sequence":"additional","affiliation":[{"name":"Department of Chemistry Sri Sathya Sai Institute of Higher Learning  Puttaparthi Andhra Pradesh 515134 India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sai Kiran","family":"Mavileti","sequence":"additional","affiliation":[{"name":"Department of Chemistry Sri Sathya Sai Institute of Higher Learning  Puttaparthi Andhra Pradesh 515134 India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Labhini","family":"Singla","sequence":"additional","affiliation":[{"name":"Department of Chemical Sciences Indian Institute of Science Education and Research Mohali, Knowledge City, Sector 81, S. 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