Skeletal hybridization and PfRIO-2 kinase modeling for synthesis of α-pyrone analogs as anti-malarial agent

• Published in: European journal of medicinal chemistry 2013-12, Vol.70, p.607-612
• Main Authors: Parveen, Afsana, Chakraborty, Arnish, Konreddy, Ananda Kumar, Chakravarty, Harapriya, Sharon, Ashoke, Trivedi, Vishal, Bal, Chandralata
• Format: Article
• Language: English
• Subjects: Anti-malarial; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Dose-Response Relationship, Drug; Induced fit docking; Models, Molecular; Molecular modeling; Molecular Structure; Oxidative Stress - drug effects; Parasitic Sensitivity Tests; Plasmodium falciparum; Plasmodium falciparum - drug effects; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Pyrone analogs; Pyrones - chemical synthesis; Pyrones - chemistry; Pyrones - pharmacology; RIO2 kinase; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2013.10.028

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. [Display omitted] Structural mapping of PfRIO2 kinase as new drug target understanding towards development of new pyrone analogs as antimalarial lead. •Pharmacophoric hybridization with computational design approach towards synthesis of new pyrone analogs.•Structural exploration of PfRIO2 kinase as plausible new anti-malarial drug target.•Active site of PfRIO2 kinase were explored for binding ability of new compounds.•SiteMap analysis of target protein for structural understanding & optimization.•The new class of lead as anti-malarial obtained for future optimization.