title: Synthesis, antimalarial activity, heme binding and docking studies of N-substituted 4-aminoquinoline-pyrimidine molecular hybrids.
abstract: A series of novel N-substituted 4-aminoquinoline-pyrimidine hybrids have been synthesized via simple and economic route and evaluated for their antimalarial activity. Most compounds showed potent antimalarial activity against both CQ-sensitive and CQ-resistant strains with high selectivity index. All the compounds were found to be non-toxic to the mammalian cell lines. The most active compound 7b was analysed for heme binding activity using UV-spectrophotometer. Compound was found to interact with heme and a complex formation between compound and heme in a 1:1 stoichiometry ratio was determined using job plots. The interaction of these hybrids was also investigated by the molecular docking studies in the binding site of wild type Pf-DHFR-TS and quadruple mutant Pf-DHFR-TS. The pharmacokinetic property analysis of best active compounds was also studied by ADMET prediction.
authors.affiliation: Department of Chemistry, University of Delhi, Delhi 110007, India.
authors.forename: Shiv Shyam
authors.initials: SS
authors.lastname: Maurya
authors.affiliation: National Centre for Natural Products Research, University of Mississippi, MS 38677, USA.
authors.forename: Shabana I
authors.initials: SI
authors.lastname: Khan
authors.affiliation: Department of Chemistry, University of Delhi, Delhi 110007, India.
authors.forename: Aparna
authors.initials: A
authors.lastname: Bahuguna
authors.affiliation: Department of Chemistry, University of Delhi, Delhi 110007, India.
authors.forename: Deepak
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Department of Chemistry, University of Delhi, Delhi 110007, India. Electronic address: dsrawat@chemistry.du.ac.in.
authors.forename: Diwan S
authors.initials: DS
authors.lastname: Rawat
mesh_terms: D000634:Aminoquinolines / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D006418:Heme / Q000378:metabolism*; D006801:Humans; D062105:Molecular Docking Simulation; D009097:Multienzyme Complexes / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D013940:Thymidylate Synthase / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D009097:Multienzyme Complexes; D011743:Pyrimidines; C056930:thymidylate synthase-dihydrofolate reductase; D006418:Heme; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; C001920:4-aminoquinoline
keywords: Aminoquinoline; Antimalarial activity; Docking studies; Heme binding activity