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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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Aminake MN,Mahajan A,Kumar V,Hans R,Wiesner L,Taylor D,de Kock C,Grobler A,Smith PJ,Kirschner M,Rethwilm A,Pradel G,Chibale K

doi

10.1016/j.bmc.2012.06.038

subject

Has Abstract

pub_date

2012-09-01 00:00:00

pages

5277-89

issue

17

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(12)00516-0

journal_volume

20

pub_type

杂志文章

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