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We report the design, synthesis, and biological testing of a series of 13 terephthalic acid\u2010based HDAC inhibitors. All compounds showed low cytotoxicity against human embryonic kidney (HEK293) cells (IC<jats:sub>50<\/jats:sub>: 8\u2013&gt;51\u2005\u03bc<jats:sc>m<\/jats:sc>), with 11 also having sub\u2010micromolar in\u2005vitro activity against drug\u2010sensitive (3D7) and multidrug\u2010resistant (Dd2) asexual blood\u2010stage <jats:italic>P.\u2005falciparum<\/jats:italic> parasites (IC<jats:sub>50<\/jats:sub>\u22480.1\u20130.5\u2005\u03bc<jats:sc>m<\/jats:sc>). A subset of compounds were examined for activity against early\u2010 and late\u2010stage <jats:italic>P.\u2005falciparum<\/jats:italic> gametocytes and <jats:italic>P.\u2005berghei<\/jats:italic> exo\u2010erythrocytic\u2010stage parasites. While only moderate activity was observed against gametocytes (IC<jats:sub>50<\/jats:sub>&gt;2\u2005\u03bc<jats:sc>m<\/jats:sc>), the most active compound (<jats:italic>N<\/jats:italic><jats:sup>1<\/jats:sup>\u2010((3,5\u2010dimethylbenzyl)oxy)\u2010<jats:italic>N<\/jats:italic><jats:sup>4<\/jats:sup>\u2010hydroxyterephthalamide, <jats:bold>1\u2009f<\/jats:bold>) showed sub\u2010micromolar activity against <jats:italic>P.\u2005berghei<\/jats:italic> exo\u2010erythrocytic stages (IC<jats:sub>50<\/jats:sub> 0.18\u2005\u03bc<jats:sc>m<\/jats:sc>) and &gt;270\u2010fold better activity for exo\u2010erythrocytic forms than for HepG2 cells. This, together with asexual\u2010stage in\u2005vitro potency (IC<jats:sub>50<\/jats:sub>\u22480.1\u2005\u03bc<jats:sc>m<\/jats:sc>) and selectivity of this compound versus human cells (SI&gt;450), suggests that <jats:bold>1\u2009f<\/jats:bold> may be a valuable starting point for the development of novel antimalarial drug leads with low host cell toxicity and multi\u2010stage anti\u2010plasmodial activity.<\/jats:p>","DOI":"10.1002\/cmdc.201700360","type":"journal-article","created":{"date-parts":[[2017,8,15]],"date-time":"2017-08-15T22:22:47Z","timestamp":1502835767000},"page":"1627-1636","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Design and Synthesis of Terephthalic Acid\u2010Based Histone Deacetylase Inhibitors with Dual\u2010Stage Anti\u2010<i>Plasmodium<\/i> Activity"],"prefix":"10.1002","volume":"12","author":[{"given":"Katharina","family":"Stenzel","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical and Medicinal Chemistry Heinrich Heine University D\u00fcsseldorf  40225 D\u00fcsseldorf Germany"},{"name":"Griffith Institute for Drug Discovery, Griffith University  Don Young Road, Nathan Campus QLD 4111 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming Jang","family":"Chua","sequence":"additional","affiliation":[{"name":"Griffith Institute for Drug Discovery, Griffith University  Don Young Road, Nathan Campus QLD 4111 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Duffy","sequence":"additional","affiliation":[{"name":"Griffith Institute for Drug Discovery, Griffith University  Don Young Road, Nathan Campus QLD 4111 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yevgeniya","family":"Antonova\u2010Koch","sequence":"additional","affiliation":[{"name":"Department of Pediatrics School of Medicine University of California, San Diego  9500 Gilman Drive 0741 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