Journal of Medicinal Chemistry · 1991 · 88 citations · 0 references
PharmacyMedicinal ChemistryPharmacologyDrug DiscoveryOrganic ChemistryStructure-activity RelationshipsAntiretroviral TherapyAntiviral PharmacologyAntiviral Prodrug DesignAntiviral TherapyLipid ChemistryStructure-activity Relationship AnalysisAntiviral Structure-activity RelationshipsLipid Conjugation ChemistryNucleoside Analog SynthesisNucleoside AnalogsNucleoside Analogue AntiviralsNucleoside Reverse Transcriptase InhibitorsNucleotide Analogue ProdrugsProdrug Lipid Conjugates
Combinations of an amidoalkylphosphocholine, 8, and AZT have been found to cause an apparent synergistic action in suppressing infectious HIV-1 replication. In addition, amidoalkyl, oxyalkyl, and thioalkyl ether lipids have been chemically linked to anti-HIV-1 nucleosides (AZT and DDI) through phosphate and phosphonate linkages. These conjugates have shown promising in vitro anti-HIV-1 activity. Also, the conjugates have a 5-10-fold reduction in cell cytotoxicity compared to AZT alone. The most active compound, an amidoalkyl ether lipid-AZT conjugates, 4A, was found to have a differential selectivity of 1793 in a syncytial plaque assay. In comparison, AZT alone has a value of 1281.