title: Design, in silico and in vitro evaluation of curcumin analogues against Plasmodium falciparum.
abstract: The polyphenolic compound curcumin has been reported for its antimalarial properties in various scientific studies. Plasmodium falciparum ATP6, the parasite orthologue of mammalian sarcoplasmic Ca2+ATPase (SERCA) has been identified as a key molecular target of both artemisinin and curcumin. The work was thereby undertaken to study the anti-malarial properties of two different series of curcumin analogues based on their docking interactions with PfATP6 and correlating the results with their anti-malarial activity. The compounds were designed retaining similar functional groups as that of the parent curcumin nucleus while incorporating changes in the carbon chain length, unsaturated groups and the number of ketone groups. The compounds (1E, 4E)-1,5-bis(4-methylphenyl)penta-1,4-dien-3-one (CD-9), (1E, 4E)-1,5-bis(4-methoxyphenyl)penta-1,4-dien-3-one (CD-8) and (E)-1,3-bis(4-hydroxylphenyl)prop-2-en-1-one (CD-1) showed IC50values of 1.642 μM, 1.764 μM and 2.59 μM in 3D7 strain and 3.039 μM, 7.40 μM and 11.3 μM in RKL-2 strain respectively. Detailed structure-activity relationship studies of the compounds showed that CD-9 and CD-8 had a common hydrophobic interaction with the residue Leu268 of the PfATP6 protein and has been postulated through our study to be the reason for their antimalarial activity as seen after corroborating the results with the in vitro study. The study provided valuable insight about the ligand-protein interaction of the various functional groups of curcumin and its analogues against the PfATP6 protein and their importance in imparting antimalarial action.
authors.affiliation: Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh 786004, India. Electronic address: chnadrajit@gmail.com.
authors.forename: Chandrajit
authors.initials: C
authors.lastname: Dohutia
authors.affiliation: Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh 786004, India.
authors.forename: Dipak
authors.initials: D
authors.lastname: Chetia
authors.affiliation: Regional Medical Research Centre NE (Indian Council of Medical Research), Dibrugarh 786001, India.
authors.forename: Kabita
authors.initials: K
authors.lastname: Gogoi
authors.affiliation: Regional Medical Research Centre NE (Indian Council of Medical Research), Dibrugarh 786001, India.
authors.forename: Kishore
authors.initials: K
authors.lastname: Sarma
mesh_terms: D000098:Acetophenones / Q000737:chemistry; D018949:Antigens, CD1 / Q000378:metabolism; D000962:Antimalarials / Q000494:pharmacology*; D001547:Benzaldehydes / Q000737:chemistry; D016827:CD8 Antigens / Q000378:metabolism; D002599:Chalcone / Q000031:analogs & derivatives; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D020128:Inhibitory Concentration 50; D008024:Ligands; D062105:Molecular Docking Simulation; D010422:Pentanones / Q000737:chemistry; D010963:Plasmodium falciparum / Q000187:drug effects*; D060245:Tetraspanin 29 / Q000378:metabolism
chemical_list: D000098:Acetophenones; D018949:Antigens, CD1; D000962:Antimalarials; D001547:Benzaldehydes; D016827:CD8 Antigens; D008024:Ligands; D010422:Pentanones; D060245:Tetraspanin 29; D002599:Chalcone; C533260:dibenzylidene acetone; D003474:Curcumin
keywords: Curcumin; PfATP6; Plasmodium falciparum; SAR; Synthesis