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The aromatic ring on the dihydropyrimidinone of the original hits was exchanged for a methyl group to bring the molecular weights below 500\u2005Da and also determine the effect of the aromatic ring count on the resistance reversal ability of the hybrids. Apart from the previously used amide bond, the hybrid linker was also extended to the triazole linker. Although the triazole linker is synthetically easier to access, the use of an amide linker seems to have an activity advantage. The synthesised compounds in addition to the previously identified hits were subjected to molecular docking particularly targeting the orthosteric site of <jats:italic>Plasmodium falciparum<\/jats:italic> glutathione reductase (<jats:italic>Pf<\/jats:italic>GR) protein. The ligand with the best binding interaction was rationally optimised to increase its suitability as a competitive inhibitor against the cofactor of the <jats:italic>Pf<\/jats:italic>GR. Two of the optimised ligands showed better binding affinities than the cofactor while one of the two ligands displayed hydrophobically packed correlated hydrogen\u2010bond which is very important in maintaining the ligand stability within the protein. <jats:italic>In silico<\/jats:italic> ADME predictions of the synthesised compounds indicate that these compounds possess good pharmacokinetic properties.<\/jats:p>","DOI":"10.1002\/cmdc.202200034","type":"journal-article","created":{"date-parts":[[2022,2,23]],"date-time":"2022-02-23T10:45:01Z","timestamp":1645613101000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Rational Optimization of Dihydropyrimidinone\u2010Quinoline Hybrids as <i>Plasmodium falciparum<\/i> Glutathione Reductase Inhibitors"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9588-4966","authenticated-orcid":false,"given":"Rasheed A.","family":"Adigun","sequence":"first","affiliation":[{"name":"Department of Chemistry University of Pretoria  Lynnwood Road, Hatfield Pretoria 0002 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2446-2165","authenticated-orcid":false,"given":"Frederick P.","family":"Malan","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Pretoria  Lynnwood Road, Hatfield Pretoria 0002 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed O.","family":"Balogun","sequence":"additional","affiliation":[{"name":"Biopolymer Modification &amp; Therapeutics Lab Chemicals Cluster Council for Scientific and Industrial Research  Meiring Naude Road, Brummeria Pretoria 0001 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5163-9267","authenticated-orcid":false,"given":"Natasha","family":"October","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Pretoria  Lynnwood Road, Hatfield Pretoria 0002 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,3,21]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2016.11.025"},{"key":"e_1_2_8_2_1","unstructured":"WHO World Malaria Report 2021. 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