Inhibition of Plasmodium falciparum Hsp90 Contributes to the Antimalarial Activities of Aminoalcohol-carbazoles

Abstract

Malaria caused by the protozoan parasite Plasmodium falciparum (Pf) remains a major public health problem throughout the developing world. One molecular target that should receive more attention is the molecular chaperone Hsp90. It is essential and highly conserved in all eukaryotes, including in protozoan parasites. We have identified an amino-alcohol carbazole (N-CBZ) as a PfHsp90-selective inhibitor by virtually docking a large set of antimalarial compounds, previously found in a phenotypic screen, into a PfHsp90-specific pocket. By correlating the ability of 30 additional N-CBZ derivatives to bind directly to PfHsp90 with their Pf-inhibitory activity, we found that these types of compounds are more likely to inhibit Pf growth if they bind PfHsp90. For plausible targets such as PfHsp90, our workflow may help identifying the molecular target for compounds found by screening large chemical libraries for a desired biological effect and, conversely, ensuring biological effectiveness for compounds affecting a particular target.

The heat shock protein 90 of Toxoplasma gondii is essential for invasion of host cells and tachyzoite growth

“…Plasmodium Hsp90 had been shown to regulate parasite growth in human erythrocytes [52]. Geldanamycin (GA) competitively binds to the N-terminal ATP-binding pocket of Hsp90, leading to the inhibition of its chaperone cycle and reducing the capacity of E. tenella to invade and grow in host cells [38].…”

Novel carbazole aminoalcohols as inhibitors of β -hematin formation: Antiplasmodial and antischistosomal activities

“…Recently, it has been reported that Plasmodium falciparum Hsp90 was a plausible target of carbazole aminoalcohols (Wang et al., 2016a, Wang et al., 2016b), while there is still no clue of their mechanism of action on schistosomes. In this work, three kinds of biological assay revealed a similar SAR pattern: (1) dichlorinated carbazole acted as a privileged core; (2) an alkylamine tail was beneficial for activity; conversely, arylamine substituents imparted negative effect to potency; and (3) stereochemistry of the secondary hydroxyl group had no influence on potency.…”

“…The obtained residues were purified by recrystallization from ethanol to afford target compounds. The characterization data of compounds 6–8 and 12–16 were reported in our previous work (Wang et al., 2016a, Wang et al., 2016b), and the characterization data of compounds 3–5 , 9–11 , ( R )-7 and ( S )-7) were given as follows.…”

“…Synthesis of carbazole aminoalcohols was performed as previously described (Wang et al., 2016a, Wang et al., 2016b). To a solution of 9-(oxiran-2-ylmethyl)-9 H -carbazole ( 2a-c , 2 mmol) in EtOH (20 mL), corresponding amines (6 mmol) were added.…”

“…Hemozoin formation occurs within the plasmodium digestive food vacuoles (pH 4.8). At relevant acidic conditions, both N atoms of compound 7 are protonated (Wang et al., 2016a, Wang et al., 2016b). Accordingly, they were charged +1 for docking simulations.…”