Quinoline Binding Site on Malaria Pigment Crystal:  A Rational Pathway for Antimalaria Drug Design

Abstract

Human malaria, one of the most striking, reemerging infectious diseases, is caused by several types of Plasmodium parasites. As the parasite digests hemoglobin in human red blood cells, the heme byproduct crystallizes into micron-sized malaria-pigment (hemozoin). Making use of a recently reported powder-crystal structure determination of synthetic hemozoin (β-hematin), we describe here its theoretical growth form and show it to be similar in habit and form to that of natural hemozoin. With this information, we propose a noncovalent binding site for the quinoline drug family at the end face of the fastest-growing direction of β-hematin. This adsorption mechanism is examined in terms of crystal growth inhibition vis-à-vis published data. The surface binding site elucidates the difference in activity of various quinolines, revealing the importance of the different quinoline functionalities. The interplay between molecular chirality of quinolines and the chirality of centrosymmetric β-hematin crystal faces is analyzed in terms of crystal growth inhibition. We additionally propose a molecular isomerism of the crystalline building blocks, with implications on quinoline surface binding, as well as on nucleation and size of β-hematin crystals.

Aligned hemozoin crystals in curved clusters in malarial red blood cells revealed by nanoprobe X-ray Fe fluorescence and diffraction

“…By asserting an average hemozoin crystal volume to be 0.0085 μm 3 , as derived from Table S1 in the companion report (13), the number of crystals in each RBC (Table 2) was estimated. It is noteworthy that the volume 0.0085 μm 3 corresponds to dimensions ≈0.13 × 0.13 × 0.45 μm 3 , given that the relative dimensions of hemozoin along its a, b, and c axes are ≈1∶1∶3.5, according to its theoretical growth habit (15).…”

Structure–activity relationships for ferriprotoporphyrin IX association and β-hematin inhibition by 4-aminoquinolines using experimental and ab initio methods

“…11 The detailed mechanism of inhibition has been a matter of debate, with one school of thought proposing that it involves complex formation in solution, [12][13][14] while another postulates inhibition of crystal growth via interaction with the crystal surface. 15 It is known that quinolines form complexes with Fe(III)PPIX in solution, 12,16 while it is also the case that the inhibitory effects of these compounds can be described by a surface interaction model. 15,17,18 4…”

“…15 It is known that quinolines form complexes with Fe(III)PPIX in solution, 12,16 while it is also the case that the inhibitory effects of these compounds can be described by a surface interaction model. 15,17,18 4…”

“…Thus, a role for solution association cannot necessarily be ruled out for all series of 4-aminoquinoline compounds. Finally, the correlation equations permit the prediction of both log K and log BHIA 50 for these series of [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] aminoquinolines. Interestingly, they do not suggest that the lipophilicity of the group X plays a major role in -hematin inhibition.…”

Comparative vibrational spectroscopic studies of 7-chloro-4- hydroxy-3-quinolinecarboxylic acid based on density functional theory

“…There is considerable evidence indicating that quinoline-based antimalarial agents such as chloroquine acts by forming toxic complexes with free hematin [7,8]. In a study by De et al,chloroquinolines with N, N'-diethyldiaminoalkane side chains with lengths between 2 and 12 carbons were found to be as effective as chloroquine against chloroquine-sensitive strains [9]. Recently, 4-aminoquinolines with different substituents at the 7-position and N-oxides quinolines were studied by De Dios et al to examine drug-heme association constants [10,11].…”