TY - JOUR
T1 - Targeting the fatty acid biosynthesis enzyme, β-ketoacyl - Acyl carrier protein synthase III (PfKASIII), in the identification of novel antimalarial agents
AU - Lee, Patricia J.
AU - Bhonsle, Jayendra B.
AU - Gaona, Heather W.
AU - Huddler, Donald P.
AU - Heady, Tiffany N.
AU - Kreishman-Deitrick, Mara
AU - Bhattacharjee, Apurba
AU - McCalmont, William F.
AU - Gerena, Lucia
AU - Lopez-Sanchez, Miriam
AU - Roncal, Norma E.
AU - Hudson, Thomas H.
AU - Johnson, Jacob D.
AU - Prigge, Sean T.
AU - Waters, Norman C.
PY - 2009/2/26
Y1 - 2009/2/26
N2 - The importance of fatty acids to the human malaria parasite, Plasmodium falciparum, and differences due to a type I fatty acid synthesis (FAS) pathway in the parasite, make it an attractive drug target. In the present study, we developed and a utilized a pharmacophore to select compounds for testing against PfKASIII, the initiating enzyme of FAS. This effort identified several PfKASIII inhibitors that grouped into various chemical classes of sulfides, sulfonamides, and sulfonyls. Approximately 60% of the submicromolar inhibitors of PfKASIII inhibited in vitro growth of the malaria parasite. These compounds inhibited both drug sensitive and resistant parasites and testing against a mammalian cell line revealed an encouraging in vitro therapeutic index for the most active compounds. Docking studies into the active site of PfKASIII suggest a potential binding mode that exploits amino acid residues at the mouth of the substrate tunnel.
AB - The importance of fatty acids to the human malaria parasite, Plasmodium falciparum, and differences due to a type I fatty acid synthesis (FAS) pathway in the parasite, make it an attractive drug target. In the present study, we developed and a utilized a pharmacophore to select compounds for testing against PfKASIII, the initiating enzyme of FAS. This effort identified several PfKASIII inhibitors that grouped into various chemical classes of sulfides, sulfonamides, and sulfonyls. Approximately 60% of the submicromolar inhibitors of PfKASIII inhibited in vitro growth of the malaria parasite. These compounds inhibited both drug sensitive and resistant parasites and testing against a mammalian cell line revealed an encouraging in vitro therapeutic index for the most active compounds. Docking studies into the active site of PfKASIII suggest a potential binding mode that exploits amino acid residues at the mouth of the substrate tunnel.
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U2 - 10.1021/jm8008103
DO - 10.1021/jm8008103
M3 - Article
C2 - 19191586
AN - SCOPUS:64349090650
SN - 0022-2623
VL - 52
SP - 952
EP - 963
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 4
ER -