title: Pharmacophore based discovery of potential antimalarial agent targeting haem detoxification pathway.
abstract: 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.
authors.affiliation: Discovery Centre, Defence Research and Development Establishment, Jhansi Road, Gwalior, Madhya Pradesh 474002, India.
authors.forename: Badri Narayan
authors.initials: BN
authors.lastname: Acharya
authors.forename: Deepika
authors.initials: D
authors.lastname: Saraswat
authors.forename: Mahabir Parshad
authors.initials: MP
authors.lastname: Kaushik
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D006418:Heme / Q000378:metabolism*; D007538:Isoniazid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D000962:Antimalarials; D054852:Small Molecule Libraries; C538761:nicotinic acid (trans-3-(4-ethoxy-3-methoxy-phenyl)-1-(4-hydroxy-phenyl)-allylidene)-hydrazide; D006418:Heme; D007538:Isoniazid