Background
Methods
Search strategy and study selection
Data extraction
Quality assessment
Results
Study selection
Characteristics of selected studies
Author/Year/Country | Chemical groups | Plasmodium falciparum strain | Anti-hemozoin assay | Correlation test | Correlation results | Risk of bias |
---|---|---|---|---|---|---|
Acharya/2010/India [21] | Pyrazoline | Chloroquine-sensitive MRC-02 | High concentration of acetate | Pearson’s r | r = 0.62a | Reliable without restrictions |
Pyrazoline (+chloroquine) | r = 0.63a | |||||
Pyrazoline | Chloroquine resistant RKL9 | r = 0.54a | ||||
Pyrazoline (+chloroquine) | r = 0.40a | |||||
Andayi/2013/South Africa [22] | Quinoline (chloroquine deprotected analogues) | Chloroquine sensitive 3D7 | Heat-induced β-haematin | R2 | R2 = 0.92 | Reliable with restrictions |
Spearman | ρ = 0.595 (p = 0.12) | |||||
Chloroquine resistant W2 | R2 | R2 = 0.95 | ||||
Spearman | ρ = 0.976 (p = 0.00003) | |||||
Chloroquine resistant K1 | Spearman | ρ = 0.643 (p = 0.119) | ||||
Quinoline (chloroquine benzylated analogues) | Chloroquine sensitive 3D7 | R2 | R2 = 0.96 | |||
Spearman | ρ = 0.464 (p = 0.294) | |||||
Chloroquine resistant W2 | R2 | R2 = 0.93 | ||||
Spearman | ρ = 0.821 (p = 0.023) | |||||
Chloroquine resistant K1 | Spearman | ρ = 0.571 (p = 0.139) | ||||
Quinoline (chloroquine methoxy analogues) | Chloroquine resistant W2 | Spearman | ρ = -0.600 (p = 0.6) | |||
Hawley/1998/UK [23] | Quinoline | Chloroquine sensitive 3D7 | Preformed β-haemozoin | Pearson’s r | r = 0.81 | Reliable with restrictions |
Chloroquine resistant K1 | r = 0.17 | |||||
Burgess/2010/USA [30] | Quinoline (Reversed chloroquinolines) | Chloroquine sensitive D6 | Tween 20-induced β-haematin | R2 | R2 = 0.66 | Not reliable |
Spearman | ρ = 0.476 (p = 0.233) | |||||
Chloroquine resistant Dd2 | Spearman | ρ = 0.574 (p = 0.183) | ||||
Chloroquine resistant 7G8 | Spearman | ρ = 0.333 (p = 0.42) | ||||
Vennerstrom/1998/USA [34] | Biquinolines | Chloroquine sensitive D6 | Preformed β-haemozoin | Pearson’s r | r = 0.29 | Not reliable |
Chloroquine resistant W2 | r = 0.55 | |||||
Chloroquine sensitive D6 Chloroquine resistant W2 | r = 0.57 | |||||
Chloroquine sensitive D6 | Spearman | ρ = 0.376 (p = 0.254) | ||||
Chloroquine resistant W2 | ρ = 0.67 (p = 0.024) | |||||
Chloroquine sensitive D6 Chloroquine resistant W2 | ρ = 0.519 (p = 0.013) | |||||
Dorn/1998/Switzerland [31] | Quinolines, quinacrine and halofantrine | Quinoline sensitive NF54 | Preformed β-haemozoin | Pearson’s r | r = 0.919 (p = 0.003) | Reliable with restrictions |
Kaschula/2002/South Africa [32] | Quinoline | Chloroquine sensitive D10 | High concentration of acetate - | R2 | R2 = 0.83a | Reliable with restrictions |
Chloroquine sensitive D10 | Spearman | ρ = 0.919a | ||||
Ignatushchenko/1997/USA [35] | Xanthone | Chloroquine sensitive D6 | Phosphate-induced β-haematin | Spearman | ρ = 0.886 (p = 0.019) | Reliable with restrictions |
Guetzoyan/2009/France [24] | Acridine | Chloroquine sensitive 3D7 | High concentration of acetate | Spearman | ρ = 0.095 (p = 0.823) | Reliable with restrictions |
Chloroquine sensitive W2 | ρ = 0.299 (p = 0.471) | |||||
Chloroquine resistant FCR3 | ρ = 0.381 (p = 0.352) | |||||
Chloroquine resistant Bre1 | ρ = 0.261 (p = 0.531) | |||||
Sandlin/2014/USA [33] | Quinoline 4-benzamidopyridine Quinazoline Phenyl benzamides Nicotinamide Carbazole Miscellaneous compounds | Chloroquine sensitive D6 | NP-40-induced β-haematin | Spearman | ρ = 0.35 (p = 0.322) | Reliable with restrictions |
Chloroquine sensitive C235 | ρ = 0.139 (p = 701) |
Risk of bias of included studies
Correlation between anti-haemozoin and anti-malarial activity
Chemical groups | Characteristics |
---|---|
Quinoline | Strong correlations between anti-haemozoin and in vitro anti-malarial activity, against sensitive strain (NF54), r = 0.919 (p = 0.003). Logarithm manner of the correlation observed between BHIA50 and normalized-IC50 values of in vitro anti-malarial activity in strain 3D10 (R2 = 0.83, Spearman ρ = 0.919) There were three compounds (with hydro-, hydroxyl-, and acetyl-radicals at 7-position) were removed from the analysis, because they had very weak anti-malarial activity (IC50 ranging from 448 to 3017 nM) and non-detectable anti-haemozoin activity Strong affinity with haem |
Quinoline (chloroquinoline) | Quite good or strong correlation between anti-haemozoin and in vitro anti-malarial activity, against sensitive strains 3D7 (R2 = 0.92–0.96, Spearman ρ = 0.464–0.595), resistant strain W2 (R2 = 0.93–0.95, Spearman ρ = 0.821–0.976). The good correlations between these two activities on 3D7 strain might be fortuitous Poorer correlations recorded for resistant strain K1 (Spearman ρ = 0. 571–0.643) A compound was removed from this analysis due to its inactivation of haemozoin formation, despite it might have good anti-malarial effect |
Quinoline (Reversed chloroquinoline) | Pretty good correlation observed when normalizing the IC50 values of in vitro anti-malarial activity, against sensitive strain D6 (R2 = 0.66, Spearman ρ = 0.476 (p = 0.233)), and resistant strain Dd2 (Spearman ρ = 0.574 (p = 0.183)) Poorer correlation observed on resistant strain 7G8 (Spearman ρ = 0.333 (p = 0.42)) A compound which had strong anti-malarial activity (IC50 = 2 nM) was removed from the analysis due to its insoluble form in anti-haemozoin test |
Xanthone | Good correlation between anti-haemozoin and in vitro anti-malarial activity in strain D6 (Spearman ρ = 0.886 (p = 0.019)) Strong affinity with haem Position 4-, and 5- in xanthone scaffold were favored to the good correlation Three compounds were removed from the analysis, namely 2-hydroxanthone, 1,3-dihydroxyxanthone, 2,3,4,5,6- pentaacetylxanthone. They were active against P. falciparum D6 strain (IC50 ranged from 0.075 to 75 µM) but did not possess the anti-haemozoin activity (IC50 > 1000 µM) |
Quinoline (biquinoline) | Modest correlation with pooled data for strains W2, D6 (R = 0.57, Spearman ρ = 0.519 (p = 0.013)) Poor correlation for strain D6 (R = 0.29, Spearman ρ = 0.376 (p = 0.254)) |
Pyrazoline | Modest correlation (r = 0.54–0.62) Logarithm manner of the correlation observed between normalized-IC50 values of in vitro anti-malarial activity (MRC-02 strain and RKL9 strain) and BHIA50. Lower correlation values happened when adding chloroquine |
Acridine | No correlation observed on strains 3D7, W2, FCR3, Bre1 (Spearman ρ = 0.095, 0.299, 0.381, 0.261, respectively) |