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The development of new, affordable antimalarial drugs is of vital importance as there are increasing reports of resistance to the currently available therapeutics. In addition, most of the current drugs used for chemoprophylaxis merely act on parasites already replicating in the blood. At this point, a patient might already be suffering from the symptoms associated with the disease and could additionally be infectious to an <jats:italic>Anopheles<\/jats:italic> mosquito. These insects act as a vector, subsequently spreading the disease to other humans. In order to cure not only malaria but prevent transmission as well, a drug must target both the blood\u2010 and pre\u2010erythrocytic liver stages of the parasite. <jats:italic>P.\u2005falciparum<\/jats:italic> (<jats:italic>Pf<\/jats:italic>) enoyl acyl carrier protein (ACP) reductase (ENR) is a key enzyme of plasmodial type\u2005II fatty acid biosynthesis (FAS\u2005II). It has been shown to be essential for liver\u2010stage development of <jats:italic>Plasmodium berghei<\/jats:italic> and is therefore qualified as a target for true causal chemoprophylaxis. Using virtual screening based on two crystal structures of <jats:italic>Pf<\/jats:italic>ENR, we identified a structurally novel class of FAS inhibitors. Subsequent chemical optimization yielded two compounds that are effective against multiple stages of the malaria parasite. These two most promising derivatives were found to inhibit blood\u2010stage parasite growth with IC<jats:sub>50<\/jats:sub> values of 1.7 and 3.0\u2005\u03bc<jats:sc>M<\/jats:sc> and lead to a more prominent developmental attenuation of liver\u2010stage parasites than the gold\u2010standard drug, primaquine.<\/jats:p>","DOI":"10.1002\/cmdc.201200407","type":"journal-article","created":{"date-parts":[[2013,1,22]],"date-time":"2013-01-22T16:15:58Z","timestamp":1358871358000},"page":"442-461","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Novel Type\u2005II Fatty Acid Biosynthesis (FAS II) Inhibitors as Multistage Antimalarial Agents"],"prefix":"10.1002","volume":"8","author":[{"given":"Florian C.","family":"Schrader","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serghei","family":"Glinca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia M.","family":"Sattler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans\u2010Martin","family":"Dahse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo A.","family":"Afanador","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean T.","family":"Prigge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Lanzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann\u2010Kristin","family":"Mueller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard","family":"Klebe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Schlitzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,1,22]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)60034-8"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1129720"},{"key":"e_1_2_6_3_2","unstructured":"World Malaria Report 2010 World Health Organization (WHO) Global Malaria Programme 2010; 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