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Modification of Triclosan Scaffold in Search of Improved Inhibitors for Enoyl‐Acyl Carrier Protein (ACP) Reductase in Toxoplasma gondii
Author(s) -
Stec Jozef,
Fomovska Alina,
Afanador Gustavo A.,
Muench Stephen P.,
Zhou Ying,
Lai BoShiun,
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.
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300050
Subject(s) - toxoplasma gondii , ic50 , triclosan , enzyme , toxoplasmosis , potency , drug , chemistry , recombinant dna , in vitro , reductase , lead compound , biochemistry , combinatorial chemistry , biology , stereochemistry , pharmacology , virology , medicine , pathology , gene , antibody , immunology
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 Toxoplasma gondii ( Tg 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 16 a and 16 c have IC 50 values of 250 n M against Toxoplasma gondii tachyzoites without apparent toxicity to the host cells. Their IC 50 values against recombinant Tg ENR were found to be 43 and 26 n M , respectively. Additionally, 11 other analogues in this series had IC 50 values ranging from 17 to 130 n M in the enzyme‐based assay. With respect to their excellent in vitro activity as well as improved drug‐like properties, the lead compounds 16 a and 16 c are deemed to be excellent starting points for the development of new medicines to effectively treat Toxoplasma gondii infections.