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

Apurba K. Bhattacharjee, Mark G. Hartell, Daniel A. Nichols, Rickey Paige Hicks, Benjamin Stanton, John E. Van Hamont, Wilbur K. Milhous

Research output: Contribution to journalArticle

93 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)59-67
Number of pages9
JournalEuropean Journal of Medicinal Chemistry
Volume39
Issue number1
DOIs
StatePublished - Jan 1 2004

Fingerprint

Antimalarials
Structure-Activity Relationship
Quinolines
Chalcones
Rhodamines
Quantitative Structure-Activity Relationship
Cyclin-Dependent Kinases
Falciparum Malaria
Hydrogen
Hydrogen bonds
Coloring Agents
Databases
Lipids
tryptanthrine
indolo(2,1-b)quinazoline

Keywords

  • Malaria
  • Pharmacophore
  • QSAR

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

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. / Bhattacharjee, Apurba K.; Hartell, Mark G.; Nichols, Daniel A.; Hicks, Rickey Paige; Stanton, Benjamin; Van Hamont, John E.; Milhous, Wilbur K.

In: European Journal of Medicinal Chemistry, Vol. 39, No. 1, 01.01.2004, p. 59-67.

Research output: Contribution to journalArticle

Bhattacharjee, Apurba K. ; Hartell, Mark G. ; Nichols, Daniel A. ; Hicks, Rickey Paige ; Stanton, Benjamin ; Van Hamont, John E. ; Milhous, Wilbur K. / 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. In: European Journal of Medicinal Chemistry. 2004 ; Vol. 39, No. 1. pp. 59-67.
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