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Updated: Sep 28, 2025

Measurement of Heme Synthesis Levels in Mammalian Cells
Published on: July 9, 2015
Adsorption to the Surface of Hemozoin Crystals: Structure-Based Design and Synthesis of Amino-Phenoxazine β-Hematin
Tania Olivier1, Leigh Loots1, Michélle Kok2
1Department of Chemistry and Polymer Science, Stellenbosch University, Private BagX1, Matieland, 7602, South Africa.
Abstract:
In silico adsorption of eight antimalarials that inhibit β-hematin (synthetic hemozoin) formation identified a primary binding site on the (001) face, which accommodates inhibitors via formation of predominantly π-π interactions. A good correlation (r2 =0.64, P=0.017) between adsorption energies and the logarithm of β-hematin inhibitory activity was found for this face. Of 53 monocyclic, bicyclic and tricyclic scaffolds, the latter yielded the most favorable adsorption energies. Five new amino-phenoxazine compounds were pursued as β-hematin inhibitors based on adsorption behaviour. The 2-substituted phenoxazines show good to moderate β-hematin inhibitory activity (<100 μM) and Plasmodium falciparum blood stage activity against the 3D7 strain. N1 ,N1 -diethyl-N4 -(10H-phenoxazin-2-yl)pentane-1,4-diamine (P2a) is the most promising hit with IC50 values of 4.7±0.6 and 0.64±0.05 μM, respectively. Adsorption energies are predictive of β-hematin inhibitory activity, and thus the in silico approach is a beneficial tool for structure-based development of new non-quinoline inhibitors.
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