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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Synthesis and evaluation of hybrid drugs for a potential HIV/AIDS-malaria combination therapy
Bioorganic and Medicinal Chemistry, Volume 20, No. 17, Year 2012
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Description
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 (IC50 = 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 (CC50 >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 20 mg/kg. © 2012 Elsevier Ltd. All rights reserved.
Authors & Co-Authors
Makoah, Nigel A.
Germany, Wurzburg
Julius-maximilians-universität Würzburg
Mahajan, Aman
South Africa, Cape Town
University of Cape Town
Kumar, Vipan
India, Amritsar
Guru Nanak Dev University
Hans, Renate Hazel
Namibia, Windhoek
University of Namibia
Wiesner, L. D.
South Africa, Cape Town
University of Cape Town
Taylor, Dale
South Africa, Cape Town
University of Cape Town
de Kock, Carmen A.
South Africa, Cape Town
University of Cape Town
Grobler, Anne F.
South Africa, Potchefstroom
North-west University
Smith, Peter John
South Africa, Cape Town
University of Cape Town
Kirschner, Marc W.
Germany, Wurzburg
Julius-maximilians-universität Würzburg
Rethwilm, Axel
Germany, Wurzburg
Julius-maximilians-universität Würzburg
Pradel, Gabriele
Germany, Wurzburg
Julius-maximilians-universität Würzburg
Chibale, Kelly
South Africa, Cape Town
University of Cape Town
Statistics
Citations: 42
Authors: 13
Affiliations: 5
Identifiers
Doi:
10.1016/j.bmc.2012.06.038
ISSN:
09680896
e-ISSN:
14643391
Research Areas
Environmental
Infectious Diseases