Conservation of antiviral activity and improved selectivity in PMEO-DAPym upon pyrimidine to triazine scaffold hopping

- PMEO-DATs have been designed as a new class of antivirals and synthesized using a novel cyanuric chloride based strategy.
- The lead PMEO-DAT selectively inhibits HIV, HBV, VZV and MoMSV.
- Polymerase sensitivity to PMEO-DAT depends inversely on the ability to discriminate between correct and mismatched bases.

Acyclic nucleoside phosphonates incorporating 2,4-diaminotriazine (DAT) as a 5-aza-analog of the 2,4-diamino-pyrimidine (DAPym) nucleobase present in PMEO-DAPyms have been synthesized. The lead PMEO-DAT is as inhibitory against HIV, HBV, MSV and VZV replication as the parent PMEO-DAPym and equally inefficient at markedly affecting replication of HSV-1, HSV-2 and HCMV. A rationale for this similar biological profile is proposed on the basis of structural differences in the active site of the viral DNA polymerases. PMEO-DAT is, however, more selective because, unlike PMEO-DAPym, it does not stimulate secretion of β-chemokines in cultured PBMC.