N-3-Hydroxylation of pyrimidine-2,4-diones was recently found to yield inhibitors of both HIV-1 reverse transcriptase (RT) and integrase (IN). An extended series of analogues featuring a benzoyl group at the C-6 position of the pyrimidine ring was synthesized. Through biochemical studies it was found that these new analogues are dually active against both RT and IN in low micromolar range. Antiviral assays confirmed that these new inhibitors are active against HIV-1 in cell culture at nanomolar to low micromolar range, further validating 3-hydroxypyrimidine-2,4-diones as a viable scaffold for antiviral development.
Bibliographical noteFunding Information:
This research was supported by the Center for Drug Design at the University of Minnesota, by the Center for Cancer Research, National Cancer Institute, NIH, and by an NIH-IATAP grant to Y.P. and K.M. We thank Roger Ptak at Southern Research Institute for antiviral assays and the Minnesota Supercomputing Institute for modeling resources.
- Dual inhibitors
- Reverse transcriptase