Correlation between anti-malarial and anti-haemozoin activities of anti-malarial compounds

Abstract

Background Despite noticeable improvement in anti-malarial treatment, rapid growth of resistant malaria strains points out the need for continuous development of novel anti-malarials to fight the disastrous infection. Haemozoin is considered as a novel inhibitory pathway for new anti-malarial drugs, therefore, this study aimed to systematically review all articles investigating the correlation between anti-malarial and anti-haemozoin activities of anti-malarial compounds. Methods A literature search was conducted on 22 October 2017 in eight databases for relevant in vitro articles reporting the correlation between anti-malarial and anti-haemozoin of anti-malarial compounds, based on the constructed search terms and inclusion criteria. ToxRtool was used to assess quality of each study. Results A total of ten articles were included in the review. In vitro anti-malarial and anti-haemozoin activity had a good correlation for quinolines for sensitive strains (R2 ranging from 0.66 to 0.95) and xanthones (Spearman ρ = 0.886). However, these correlations were reached after removing some compounds which had non-detectable anti-malarial or anti-haemozoin effects. Other structures (acridines, pyrolidines) showed negligible correlation with Spearman ρ ranging from 0.095 to 0.381 for acridines, and r varying from 0.54 to 0.62 for pyrolidines. Some good correlations were only shown in a logarithmic manner or when the anti-malarial activity was normalized. Conclusion The results raised a relative relationship between anti-haemozoin and in vitro anti-malarial activities. Some studies reported compounds that were effective in the inhibition of haemozoin formation, but failed to inhibit the parasite survival and vice versa. The correlation results in these studies were calculated after these compounds were removed from their analysis. The ability of anti-malarial compounds to accumulate inside the reaction site might strengthen their anti-malarial activity.

Adsorption to the Surface of Hemozoin Crystals: Structure‐Based Design and Synthesis of Amino‐Phenoxazine β‐Hematin Inhibitors

“…This was necessary as in the original descriptions of the assay, only the activities of CQ and AQ are reported. A strong correlation (r 2 =0.95, P=0.0002) is observed between the β‐hematin IC 50 values and the asexual antiplasmodium activity against the chloroquine‐sensitive 3D7 strain ( Figure S3a ), which is consistent with previous studies [27,29] . We next investigated correlations between β‐hematin IC 50 values and adsorption energy values.…”

“…[25] This mode of action has been inferred from β-hematin studies for the remaining five drugs, [26] although some inconsistencies are noted for acridine compounds such as QC. [27] All antimalarial drugs investigated in the in silico study were purchased and (re)tested for synthetic HZ (β-hematin) inhibitory activity using a biomimetic detergent (NP-40) assay, [28] the results of which are reported in Table S9. This was necessary as in the original descriptions of the assay, only the activities of CQ and AQ are reported.…”

“…A strong correlation (r 2 = 0.95, P = 0.0002) is observed between the β-hematin IC 50 values and the asexual antiplasmodium activity against the chloroquine-sensitive 3D7 strain (Figure S3a), which is consistent with previous studies. [27,29] We next investigated correlations between βhematin IC 50 values and adsorption energy values. The latter were weighted based on the fractional abundance (> 5%) of different protic species at pH 4.8 (Table S3) and added together to obtain a single adsorption energy value for each drug (Table S9).…”

2D-quantitative structure–activity relationships model using PLS method for anti-malarial activities of anti-haemozoin compounds

“…The anti-malarial activities of various groups of compounds, in particular quinine and its derivatives, had a satisfactory correlation with their anti-haemozoin activity [ 18 ]. Haemozoin is formed inside the food vacuoles of parasites to prevent lethal toxicity of haem, which is a product of the catabolism of haemoglobin.…”

“…These approaches include the high-throughput screening (HTS) of anti-malarial drugs based on their physicochemical properties of haemozoin formation, or building computational models for in silico to screen novel anti-malarial drugs, or analog development from natural compounds or existing agents [ 19 ]. Of which, prediction models of correlation between anti-haemozoin and anti-malarial activities strongly assist in anti-malarial drug discovery, from modifying known compounds to identifying new chemical scaffolds for different targets of a large diverse database of compounds [ 18 ]. However, there is no QSAR model for anti-malarial activity of anti-haemozoin inhibitors.…”