SAR and pharmacophore models for the rhodanine inhibitors of Plasmodium falciparum enoyl-acyl carrier protein reductase.
Significance of type II fatty acid synthase pathway in the life cycle of malarial parasite has long been established. Enoyl acyl carrier protein (ACP) reductase of Plasmodium falciparum (PfENR) is the rate determining enzyme of its elongation module. Hence, PfENR has been a target for the development of antimalarials as well as vaccines. Towards this endeavour, we had recently identified rhodanine class of compounds as inhibitors of PfENR. Here, we report a number of new inhibitors belonging to this class. These inhibitors have been divided into two broad subclasses: rhodanine-furans and rhodanine-phenyls. The inhibitory activity of all compounds was determined against purified PfENR. IC(50) of these compounds were found to be in nanomolar to low-micromolar range. The structure-activity relationship of both the classes has been explored in detail for the first time. Separate 3D pharmacophore models for this enzyme have been generated for both rhodanine furans and phenyls. The pharmacophore model for rhodanine furan has a Hydrogen bond donor, two Hydrogen bond acceptors, two metal ligators, three hydrophobic, and two aromatic ring features, whereas the pharmacophore model for the phenyl subclass has two hydrogen bond donors, two hydrogen bond acceptor, a metal ligator, two hydrophobic, and two aromatic ring features. These models could be used for in silico screening of compound libraries for PfENR inhibitors.
Kumar
Gyanendra
G
National Institute of Immunology, New Delhi, India.
Banerjee
Tanushree
T
Kapoor
Neha
N
Surolia
Namita
N
Surolia
Avadhesha
A
D000962:Antimalarials / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors*; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D010963:Plasmodium falciparum / Q000201:enzymology*; D012236:Rhodanine / Q000031:analogs & derivatives* / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000962:Antimalarials; D012236:Rhodanine; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)