Design, synthesis and evaluation of 4-aminoquinoline-purine hybrids as potential antiplasmodial agents

• Published in: European journal of medicinal chemistry Vol. 126; pp. 675 - 686
• Main Authors: Reddy, P. Linga, Khan, Shabana I., Ponnan, Prija, Tripathi, Mohit, Rawat, Diwan S.
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 27.01.2017; Elsevier
• Subjects: Aminoquinoline; Aminoquinolines - chemistry; Aminoquinolines - pharmacology; Animals; Antimalarial hybrids; Antimalarials - chemistry; Antimalarials - pharmacology; Antiplasmodial activity; Binding Sites; Chemistry, Medicinal; Docking studies; Drug Resistance, Fungal; Heme - metabolism; Heme binding activity; Humans; Hypoxanthine Phosphoribosyltransferase - metabolism; Life Sciences & Biomedicine; Molecular Docking Simulation; Pharmacology & Pharmacy; Plasmodium falciparum - drug effects; Purines - chemistry; Purines - pharmacology; Science & Technology; Aminoquinoline; Docking studies; Heme binding activity; Antiplasmodial activity; Antimalarial hybrids; DOCKING; FERRIPROTOPORPHYRIN-IX; 6-OXOPURINE PHOSPHORIBOSYLTRANSFERASES; ACYCLIC NUCLEOSIDE PHOSPHONATES; PLASMODIUM-FALCIPARUM; MOLECULAR HYBRIDS; PURINE SALVAGE; ANTIMALARIAL ACTIVITY; INHIBITORS; HEME-BINDING
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.11.057

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. [Display omitted] •A series of novel 4-aminoquinoline-purine hybrids was synthesized.•Potent antiplasmodial activity against CQ-sensitive and CQ-resistant strains.•Up to six-fold better activity than reference drug (CQ) against resistant strain.•Mechanistic heme-binding studies showed 1:1 binding stoichiometry.•Computational docking studies with HGPRT protein revealed good binding interactions.