Structure-activity relationship study of antimalarial indolo [2,1-b]quinazoline-6,12-diones (tryptanthrins). Three dimensional pharmacophore modeling and identification of new antimalarial candidates.
A widely applicable three-dimensional QSAR pharmacophore model for antimalarial activity was developed from a set of 17 substituted antimalarial indolo[2,1-b]quinazoline-6,12-diones (tryptanthrins) that exhibited remarkable in vitro activity (below 100 ng/mL) against sensitive and multidrug-resistant Plasmodium falciparum malaria. The pharmacophore, which contains two hydrogen bond acceptors (lipid) and two hydrophobic (aromatic) features, was found to map well onto many well-known antimalarial drug classes including quinolines, chalcones, rhodamine dyes, Pfmrk cyclin dependent kinase inhibitors, malarial FabH inhibitors, and plasmepsin inhibitors. The phamacophore allowed searches for new antimalarial candidates from multiconformer 3D databases and enabled custom designed synthesis of new potent analogues.
Department of Medicinal Chemistry, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910-7500, U.S.A. apurba.bhattacharjee@na.amedd.army.mil
Apurba K
AK
Bhattacharjee
Mark G
MG
Hartell
Daniel A
DA
Nichols
Rickey P
RP
Hicks
Benjamin
B
Stanton
John E
JE
van Hamont
Wilbur K
WK
Milhous
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D006860:Hydrogen Bonding; D021621:Imaging, Three-Dimensional; D008958:Models, Molecular; D008968:Molecular Conformation; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D000962:Antimalarials; D011799:Quinazolines; C046243:tryptanthrine