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The efficacy of these inhibitors against<jats:italic>p.f.<\/jats:italic>-ChoK is investigated using enzymatic and<jats:italic>in vitro<\/jats:italic>assays. While MN58b may enter the choline\/phosphocholine binding site, RSM-932A appears to have an altogether novel mechanism of inhibition and is synergistic with respect to both choline and ATP. A model of inhibition for RSM-932A in which this inhibitor traps<jats:italic>p.f.<\/jats:italic>-ChoK in a phosphorylated intermediate state blocking phosphate transfer to choline is presented. Importantly, MN58b and RSM-932A have<jats:italic>in vitro<\/jats:italic>inhibitory activity in the low nanomolar range and are equally effective against chloroquine-sensitive and chloroquine-resistant strains. RSM-932A and MN58b significantly reduced parasitemia and induced the accumulation of trophozoites and schizonts, blocking intraerythrocytic development and interfering with parasite egress or invasion, suggesting a delay of the parasite maturation stage. The present data provide two new potent structures for the development of antimalarial compounds and validate<jats:italic>p.f.<\/jats:italic>-ChoK as an accessible drug target against the parasite.<\/jats:p>","DOI":"10.1128\/aac.00920-13","type":"journal-article","created":{"date-parts":[[2013,9,17]],"date-time":"2013-09-17T03:45:54Z","timestamp":1379389554000},"page":"5878-5888","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":28,"title":["Antiplasmodial Activity and Mechanism of Action of RSM-932A, a Promising Synergistic Inhibitor of Plasmodium falciparum Choline Kinase"],"prefix":"10.1128","volume":"57","author":[{"given":"Tahl","family":"Zimmerman","sequence":"first","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Moneriz","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine, Universidad de Cartagena, Cartagena, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amalia","family":"Diez","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology IV and Instituto de Investigaci\u00f3n Hospital 12 de Octubre, Universidad Complutense de Madrid, Ciudad Universitaria, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Manuel","family":"Bautista","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology IV and Instituto de Investigaci\u00f3n Hospital 12 de Octubre, Universidad Complutense de Madrid, Ciudad Universitaria, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"G\u00f3mez del Pulgar","sequence":"additional","affiliation":[{"name":"Division of Translational Oncology, Health Research Institute and University Hospital Fundaci\u00f3n Jim\u00e9nez-D\u00edaz, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arancha","family":"Cebri\u00e1n","sequence":"additional","affiliation":[{"name":"Division of Translational Oncology, Health Research Institute and University Hospital Fundaci\u00f3n Jim\u00e9nez-D\u00edaz, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Carlos","family":"Lacal","sequence":"additional","affiliation":[{"name":"Division of Translational Oncology, Health Research Institute and University Hospital Fundaci\u00f3n Jim\u00e9nez-D\u00edaz, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","first-page":"419","article-title":"Choline kinase: a novel target for antitumor drugs","volume":"4","author":"Lacal JC","year":"2001","unstructured":"LacalJC. 2001. 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