Novel piperidinylpyrimidine derivatives as inhibitors of HIV-1 LTR activation

Piperidinylpyrimidine derivatives were found to inhibit HIV-1 LTR transactivation. SAR indicated that the piperonyloyl on the nitrogen of piperidine and lipophilic substitution at pyrimidine C(6)-position are important for this inhibition. Piperidinylpyrimidine derivatives, previously prepared as inhibitors of TNF-α production, were evaluated for their inhibitory activity against HIV-1 LTR activation. Some of these derivatives inhibited activation of HIV-1 LTR-directed CAT gene expression induced by PMA in Jurkat cells. In this report, we describe SAR in this series of compounds and show that the 3,4-methylenedioxybenzoyl (piperonyloyl) group on the nitrogen of piperidine and lipophilic substitution at the C(6)-position of pyrimidine are important for this inhibitory activity. Some of the synthesized compounds also inhibited HIV-1 LTR transactivation induced by viral protein Tat. These results suggest that piperidinylpyrimidines are useful as potent AIDS therapeutics that directly inhibit HIV-1 LTR activation and indirectly suppress TNF-α production.