Modification of Triclosan Scaffold in Search of Improved Inhibitors for Enoyl‐Acyl Carrier Protein (ACP) Reductase in Toxoplasma gondii. Issue 7 (14th June 2013)

• Record Type: Journal Article
• Authors: Stec, Jozef; Fomovska, Alina; Afanador, Gustavo A.; Muench, Stephen P.; Zhou, Ying; Lai, Bo‐Shiun; El Bissati, Kamal; Hickman, Mark R.; Lee, Patty J.; Leed, Susan E.; Auschwitz, Jennifer M.; Sommervile, Caroline; Woods, Stuart; Roberts, Craig W.; Rice, David; Prigge, Sean T.; McLeod, Rima; Kozikowski, Alan P.
• Is Part Of: ChemMedChem. Volume 8:Issue 7(2013:Jul.)
• Page Start: 1138
• Page End: 1160
• Publication Date: 2013-06-14
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201300050
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>Through our focused effort to discover new and effective agents against toxoplasmosis, a structure‐based drug design approach was used to develop a series of potent inhibitors of the enoyl‐acyl carrier protein (ACP) reductase (ENR) enzyme in <italic>Toxoplasma gondii</italic> (<italic>Tg</italic>ENR). Modifications to positions 5 and 4′ of the well‐known ENR inhibitor triclosan afforded a series of 29 new analogues. Among the resulting compounds, many showed high potency and improved physicochemical properties in comparison with the lead. The most potent compounds <bold>16 a</bold> and <bold>16 c</bold> have IC₅₀ values of 250 n<sc>M</sc> against <italic>Toxoplasma gondii</italic> tachyzoites without apparent toxicity to the host cells. Their IC₅₀ values against recombinant <italic>Tg</italic>ENR were found to be 43 and 26 n<sc>M</sc>, respectively. Additionally, 11 other analogues in this series had IC₅₀ values ranging from 17 to 130 n<sc>M</sc> in the enzyme‐based assay. With respect to their excellent in vitro activity as well as improved drug‐like properties, the lead compounds <bold>16 a</bold> and <bold>16 c</bold> are deemed to be excellent starting points for the development of new medicines to effectively treat <italic>Toxoplasma gondii</italic> infections.</p> </abstract>