title: Skeletal hybridization and PfRIO-2 kinase modeling for synthesis of α-pyrone analogs as anti-malarial agent.
abstract: The pharmacophoric hybridization and computational design approach were applied to generate a novel series of α-pyrone analogs as plausible anti-malarial lead candidate. A putative active site in flexible loop close to wing-helix domain of PfRIO2 kinase was explored computationally to understand the molecular basis of ligand binding. All the synthesized molecules (3a-g) exhibited in vitro antimalarial activity. Oxidative stress induced by 3a-d were calculated and found to be significantly higher in case of 3b. Therefore, 3b, which shown most significant result was identified as promising lead for further SAR study to develop potent anti-malarials.
authors.affiliation: Department of Applied Chemistry, Birla Institute of Technology, Mesra, Ranchi 835215, India.
authors.forename: Afsana
authors.initials: A
authors.lastname: Parveen
authors.forename: Arnish
authors.initials: A
authors.lastname: Chakraborty
authors.forename: Ananda Kumar
authors.initials: AK
authors.lastname: Konreddy
authors.forename: Harapriya
authors.initials: H
authors.lastname: Chakravarty
authors.forename: Ashoke
authors.initials: A
authors.lastname: Sharon
authors.forename: Vishal
authors.initials: V
authors.lastname: Trivedi
authors.forename: Chandralata
authors.initials: C
authors.lastname: Bal
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008958:Models, Molecular; D015394:Molecular Structure; D018384:Oxidative Stress / Q000187:drug effects; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011753:Pyrones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D047428:Protein Kinase Inhibitors; D011753:Pyrones; D017346:Protein Serine-Threonine Kinases
keywords: ATP; Anti-malarial; DNA; Induced fit docking; Molecular modeling; PfRIO2 kinase; Plasmodium falciparum; Plasmodium falciparum RIO2 kinase; Pyrone analogs; RIO2 kinase; adenosine triphosphate; deoxyribonucleic acid; right open reading frame 2 kinase; w-HTH; wing helix domain