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 P. Hicks, Benjamin Stanton, John E. Van Hamont, Wilbur K. Milhous

Research output: Contribution to journalArticle

100 Scopus citations

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 2004

Keywords

  • Malaria
  • Pharmacophore
  • QSAR

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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