Linear free energy relationships predict coordination and π-stacking interactions of small molecules with ferriprotoporphyrin IX

An atomic scale mechanism for the antimalarial action of chloroquine from density functional theory calculations

“…Hence, the calculated aqueous complexation energies given in Table 1 are probably underestimated by similar amounts. Experimental studies have shown that such π-stacking interactions are weaker in less polar solvents such as octanol [25].…”

“…1 (c)]. As usual, these values neglect the favourable π-π stacking contribution, which should be in the region of 4 kcal mol -1 for aqueous solution [24] and rather less than this for a lipid-rich environment [25]. Hence, this form of the complex should be accessible in the environment provided by the parasite's digestive vacuole, and can then be deprotonated to the charge-neutral form most suited to adsorption on the surface of haemozoin crystals.…”

Effects of the angiotensin II Ala-scan analogs in erythrocytic cycle of Plasmodium falciparum (in vitro) and Plasmodium gallinaceum (ex vivo)

“…However, only Phe 8 and Tyr 4 substitutions presented the lower activity in P. falciparum erythrocytic culture. Kuter et al have described that aromatic rings present in the Phe 8 and Tyr 4 residues and found that they are indispensable to anti-malarial compounds due to π-stacking binding (Kuter et al, 2011) and indicated that the aromatic rings play a major role in peptide interactions (Moll et al, 1999;Piriou et al, 1980), as described by Silva et al (2014).…”

Synthesis, β-hematin inhibition studies and antimalarial evaluation of dehydroxy isotebuquine derivatives against Plasmodium berghei

“…[21][22][23] It is not well known how quinoline drugs target heme to inhibit haemozoin formation in vivo, and even nor is it understood whether different quinoline antimalarials inhibit haemozoin through similar or different pathways. 21 Despite there is still some controversy, it has been shown that the inhibition of haemozoin growth will depend on drug accumulation inside the parasite digestive vacuole, where it can target the soluble forms of hematin monomer or dimer [24][25][26] and/or the haemozoin crystal face {0.01}. 27,28 Recently, it has been shown for quinoline related drugs (including chloroquine) that in vitro drug-heme interactions leading to the inhibition of b-hematin correlated with parasite growth inhibition (cytostatic activity) and suggested they do not necessarily affect the cytocidal potency.…”