Insights into structural and physicochemical properties required for β-hematin inhibition of privileged triarylimidazoles

Abstract

In this study, we investigated a series of triarylimidazoles, in an effort to elucidate critical SAR information pertaining to their anti-plasmodial and β-hematin inhibitory activity. Our results showed that in addition to the positional effects of ring substitution, subtle changes to lipophilicity and imidazole ionisability were important factors in SAR interpretation. Finally, in silico adsorption analysis indicated that these compounds exert their effect by inhibiting β-hematin crystal growth at the fast growing 001 face.

Fig. 1. Cell viability (%) of P. falciparum (3D7 strain) and HeLa cells after incubation with compounds 19–45 at 20 μM for 48 hours. IC₅₀ assessment was conducted for compounds, which inhibited cell viability below the 10% threshold against P. falciparum 3D7. In general, these compounds did not display significant HeLa cytotoxicity.

Fig. 2. Plot of β-hematin IC₅₀ values for compounds 19, 32, 36 and 44vs. calculated adsorption energy at the four faces of the β-hematin crystal. A statistically significant, linear correlation (r² = 0.995, P-stat = 0.0023 ≪ 0.05) in the case of the 001 face indicates that this is the likely site of adsorption.

Fig. 3. Docked poses of compounds 32 (top) and 44 (bottom) in the 001 face groove. Interacting aromatic residues are highlighted in blue and hydrophobic residues highlighted in red. The A-ring, imidazole and B-ring of compound 32 orientate toward the crystal face, forming π-stacking and hydrophobic interactions. Compound 44 occupies a slightly different region of the groove, with the indole ring intercalating inside the groove, and the B-ring interacting with the hydrophobic region outside the corrugated groove.

Fig. 4. Plot of pIC₅₀ in the β-hematin assay vs. clog P. Compounds highlighted in black feature a single ring substituent, while those in blue (no anti-plasmodial IC₅₀) and red (anti-plasmodial IC₅₀) contain two substituents, with at least one appearing in the para position on the A-ring. Orange rings represent those compounds with methoxy substituents. Green numbers denote predicted substituent induced Δ-partial charge on the basic imidazole nitrogen comparted to unsubstituted triarylimidazole.