Synthesis and evaluation of hybrid drugs for a potential HIV/AIDS-malaria combination therapy

• Published in: Bioorganic & medicinal chemistry 2012-09, Vol.20 (17), p.5277-5289
• Main Authors: Aminake, Makoah N., Mahajan, Aman, Kumar, Vipan, Hans, Renate, Wiesner, Lubbe, Taylor, Dale, de Kock, Carmen, Grobler, Anne, Smith, Peter J., Kirschner, Marc, Rethwilm, Axel, Pradel, Gabriele, Chibale, Kelly
• Format: Article
• Language: English
• Subjects: Acquired Immunodeficiency Syndrome - drug therapy; Animals; Anti-HIV Agents - administration & dosage; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - pharmacology; antimalarials; Antimalarials - administration & dosage; Antimalarials - chemical synthesis; Antimalarials - pharmacology; Biological and medical sciences; chemistry; Combination therapy; Dose-Response Relationship, Drug; Drug metabolism; Drug Therapy, Combination; drugs; HeLa Cells; HIV Infections - drug therapy; HIV-1 - drug effects; HIV/AIDS; Human immunodeficiency virus; Humans; Hybrid drugs; Malaria; Malaria - drug therapy; Male; Medical sciences; Medicinal chemistry; Mice; Mice, Inbred C57BL; mixed infection; Molecular Structure; oral administration; Parasitic Sensitivity Tests; Pharmacokinetics; Pharmacology. Drug treatments; Plasmodium berghei; Plasmodium falciparum; Plasmodium falciparum - drug effects; risk; Structure-Activity Relationship; therapeutics; toxicity
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2012.06.038

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=26nM, SI>3000), a moderate activity against HIV (IC50=2.9μM; SI>35) and not toxic to HeLa cells at concentrations used in the assay (CC50>100μM). 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.