Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
|ABSTRACT - Internet Electron. J. Mol. Des. November 2005, Volume 4, Number 11, 751-764|
Evaluation of 4-Azaindolo[2,1-b]quinazoline-6,12-diones' Interaction with Hemin
and Hemozoin: A Spectroscopic, X-ray Crystallographic and Molecular Modeling Study
Rickey P. Hicks, Daniel A. Nichols, Charles A. DiTusa, David J. Sullivan, Mark G. Hartell, Brandon W. Koser, and Apurba K. Bhattacharjee
Internet Electron. J. Mol. Des. 2005, 4, 751-764
The 4-azaindolo[2,1-b]quinazoline-6,12-dione class of compounds
(tryptanthrins) exhibited very strong in vitro activity against
Plasmodium falciparum, as well as low cytotoxicity. Due to the
structural similarity of the 4-azaindolo[2,1-b]quinazoline-6,12-diones
with another potent antimalarial compound, chloroquine,
which is known to interact with heme, the potential interactions
between these compounds and heme were investigated. A series of
six substituted 4-azaindolo[2,1-b]quinazoline-6,12-dione analogs at
the 8 or 9-position were synthesized and their hemin binding affinity
was determined by 1H NMR methods. The X-ray crystal structure of
a representative analogue exhibits intermolecular interactions that
suggests the possibility of a heme-tryptanthrin stacking organization.
This observation is consistent for proposed interactions with hemin.
Ab initio quantum chemical calculations at the RHF/6 31G** level
were conducted to aid in the understanding of the binding process.
The ability of these compounds to inhibit haematin crystallization
was determined using IR methods. While all investigated analogs
bind via a non-covalent interaction to hemin, only the 8-nitro analog
inhibited haematin crystallization.