| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 5822551 | Antiviral Research | 2011 | 4 Pages |
Structure-activity relationship evaluation of seventy-four 2,4(1H,3H)-pyrimidinedione derivatives identified seven lead compounds based on anti-HIV-1 potency, extended range of action to include HIV-2, virus entry inhibition, reverse transcriptase inhibition, and lack of cytotoxicity to human cells. The selected pyrimidinedione congeners are highly active inhibitors of HIV-1 with EC50 values ranging from 0.6 to 2Â nM in CEM-SS cells infected with laboratory derived viruses, 11-20Â nM in fresh human PBMCs infected with subtype B (HT/92/599) virus, and 2-7Â nM in PBMCs infected with the clinical subtype C (ZA/97/003) virus. Combination antiviral assays were performed using the laboratory adapted RF strain of HIV-1 in CEM-SS cells and with a clade B and C low passage clinical isolate in fresh human peripheral mononuclear cells and the compound interactions were analyzed using MacSynergy II. The seven pyrimidinedione compounds resulted in additive to synergistic interactions in combination with entry and fusion inhibitors, nonnucleoside and nucleoside reverse transcriptase inhibitors, and the protease inhibitors. No evidence of antagonistic antiviral activity or synergistic cytotoxicity was detected with the combinations of compounds tested. The dual mechanism of action of the pyrimidinediones resulting in inhibition of both virus entry and reverse transcription suggests excellent potential of these lead pyrimidinediones as candidates for combination therapy with other approved HIV inhibitors of varying mechanism of action.
⺠The PYD congeners are highly potent dual-acting inhibitors of HIV-1 and HIV-2. ⺠The PYDs interact in an additive to synergistic manner with other anti-HIV agents. ⺠Antagonism or synergistic toxicity was not observed with the PYD combinations. ⺠The optimal PYD combinations are distinct for subtype B and subtype C HIV. ⺠PYDs with cyclopropyl substitutions appear to represent the best lead compounds.
