title: Synthesis and evaluation of hybrid drugs for a potential HIV/AIDS-malaria combination therapy.
abstract: Malaria and HIV are among the most important global health problems of our time and together are responsible for approximately 3 million deaths annually. These two diseases overlap in many regions of the world including sub-Saharan Africa, Southeast Asia and South America, leading to a higher risk of co-infection. In this study, we generated and characterized hybrid molecules to target Plasmodium falciparum and HIV simultaneously for a potential HIV/malaria combination therapy. Hybrid molecules were synthesized by the covalent fusion of azidothymidine (AZT) with dihydroartemisinin (DHA), a tetraoxane or a 4-aminoquinoline derivative; and the small library was tested for antiviral and antimalarial activity. Our data suggests that compound 7 is the most potent molecule in vitro, with antiplasmodial activity comparable to that of DHA (IC(50)=26 nM, SI>3000), a moderate activity against HIV (IC(50)=2.9 μM; SI>35) and not toxic to HeLa cells at concentrations used in the assay (CC(50)>100 μM). Pharmacokinetics studies further revealed that compound 7 is metabolically unstable and is cleaved via O-dealkylation. These studies account for the lack of in vivo efficacy of compound 7 against the CQ-sensitive Plasmodium berghei N strain in mice, when administered orally at 20mg/kg.
authors.affiliation: University of Würzburg, Research Center for Infectious Diseases, Josef-Schneider-Str. 2/D15, 97080 Würzburg, Germany.
authors.forename: Makoah N
authors.initials: MN
authors.lastname: Aminake
authors.forename: Aman
authors.initials: A
authors.lastname: Mahajan
authors.forename: Vipan
authors.initials: V
authors.lastname: Kumar
authors.forename: Renate
authors.initials: R
authors.lastname: Hans
authors.forename: Lubbe
authors.initials: L
authors.lastname: Wiesner
authors.forename: Dale
authors.initials: D
authors.lastname: Taylor
authors.forename: Carmen
authors.initials: C
authors.lastname: de Kock
authors.forename: Anne
authors.initials: A
authors.lastname: Grobler
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.forename: Marc
authors.initials: M
authors.lastname: Kirschner
authors.forename: Axel
authors.initials: A
authors.lastname: Rethwilm
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pradel
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D000962:Antimalarials / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008288:Malaria / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D000962:Antimalarials