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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

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Abstract:
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.

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