title: Design, synthesis and evaluation of 4-aminoquinoline-purine hybrids as potential antiplasmodial agents.
abstract: A novel series of 4-aminoquinoline-purine hybrids were synthesized and assessed for their antiplasmodial activity against CQ-sensitive and CQ-resistant strains of P. falciparum. It was envisaged that linking of the 4-aminoquinoline pharmacophore (targeting heme-detoxification pathway of malarial parasite) with the purine functionality (targeting plasmodial HG(X)PRT enzyme) will produce a hybrid antiplasmodial agent with increased potency. The synthesized hybrids displayed good antiplasmodial activities against both the sensitive and resistant strains of P. falciparum with up to six-fold better activity (compound 10i, IC50: 0.08 μM) compared to the reference drug CQ (IC50: 0.5 μM) against the resistant strain. The synthesized compounds were also checked for their cytotoxicity towards mammalian cells and with the exception of two compounds out of the twenty synthesized hybrids, all others were non-cytotoxic up to 11.86 μM concentration. Mechanistic heme-binding studies were performed to identify the mechanism of action of the synthesized molecules and good binding interactions were observed. Computational docking studies showed that the most active hybrids dock well within the binding site of HGPRT protein. In silico ADME predictions of the most active hybrids showed that these compounds possess good pharmacokinetic behavior.
authors.affiliation: Department of Chemistry, University of Delhi, Delhi 110007, India.
authors.forename: P Linga
authors.initials: PL
authors.lastname: Reddy
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: Prija
authors.initials: P
authors.lastname: Ponnan
authors.affiliation: Department of Chemistry, University of Delhi, Delhi 110007, India.
authors.forename: Mohit
authors.initials: M
authors.lastname: Tripathi
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 / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D025141:Drug Resistance, Fungal; D006418:Heme / Q000378:metabolism; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000378:metabolism; D062105:Molecular Docking Simulation; D010963:Plasmodium falciparum / Q000187:drug effects*; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D011687:Purines; D006418:Heme; D007041:Hypoxanthine Phosphoribosyltransferase; C001920:4-aminoquinoline
keywords: Aminoquinoline; Antimalarial hybrids; Antiplasmodial activity; Docking studies; Heme binding activity