Adsorption to the Surface of Hemozoin Crystals: Structure-Based Design and Synthesis of Amino-Phenoxazine beta-Hematin Inhibitors

In silico adsorption of eight antimalarials that inhibit beta-hematin (synthetic hemozoin) formation identified a primary binding site on the (001) face, which accommodates inhibitors via formation of predominantly pi-pi interactions. A good correlation (r(2)=0.64, P=0.017) between adsorption energies and the logarithm of beta-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 beta-hematin inhibitors based on adsorption behaviour. The 2-substituted phenoxazines show good to moderate beta-hematin inhibitory activity (<100 mu M) and Plasmodium falciparum blood stage activity against the 3D7 strain. N-1,N-1-diethyl-N-4-(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 mu M, respectively. Adsorption energies are predictive of beta-hematin inhibitory activity, and thus the in silico approach is a beneficial tool for structure-based development of new non-quinoline inhibitors.