Pharmacophore based discovery of potential antimalarial agent targeting haem detoxification pathway

Pharmacophore hypotheses were generated from molecules having putative antimalarial activities targeting haem detoxification pathway of malarial parasite. A training set consisting of 33 compounds, whose activities were evaluated for haem polymerization inhibition and against chloroquine resistant (K1) strain of Plasmodium falciparum, was optimized to generate hypotheses. The hypothesis showing optimum correlation between actual and estimated activities was validated by Fischer's randomization test at 95% confidence level and used as a model to screen our in-house compound database. Nicotinic acid [trans-3-(4-ethoxy-3-methoxy-phenyl)-1-(4-hydroxy-phenyl)-allylidene]-hydrazide (ALH5) was obtained as a hit. The compound was synthesized and evaluated against chloroquine sensitive (MRC-02) and resistant (RKL9) strains of malarial parasite P. falciparum. The compound showed antimalarial activity in nanomolar range and was found comparable with chloroquine.

Graphical abstract A quantitative pharmacophore model was developed and used as a screening tool to discover a new antimalarial agent. Nicotinic acid [trans-3-(4-ethoxy-3-methoxyphenyl)-1-(4-hydroxy-phenyl)allylidene]-hydrazide was obtained as a hit molecule. The compound was synthesized and evaluated against chloroquine sensitive and resistant strains of Plasmodium falciparum. The compound was found effective against P. falciparum and showed comparable activity with chloroquine.Figure optionsDownload full-size imageDownload as PowerPoint slide