Fused heterocycles bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 3: Optimization of [1,2,4]triazolo[1,5-a]pyrimidine core via structure-based and physicochemical property-driven approaches

• Novel [1,2,4]triazolo[1,5-a]pyrimidines were identified as potent HIV-1 inhibitors.
• 7d exhibited anti-HIV-1 activity with EC50 values of 8.1 nM (wt) and 13 μM (RES056).
• Log P and water solubility of 7d were measured.
• Preliminary SARs and molecular simulation of these new analogs were detailed.

In our arduous efforts to develop new potent HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs), novel piperidine-linked [1,2,4]triazolo[1,5-a]pyrimidine derivatives were designed, synthesized and evaluated for their antiviral activities in MT-4 cell cultures. Biological results showed that all of the title compounds displayed moderate to excellent activities against wild-type (wt) HIV-1 strain (IIIB) with EC50 values ranging from 8.1 nM to 2284 nM in a cell-based assay. Among them, the most promising analog 7d possessed an EC50 value of 8.1 nM against wt HIV-1, which was much more potent than the reference drugs DDI, 3 TC, NVP and DLV. Additionally, 7d demonstrated weak activity against the double mutant HIV-1 strain (K103N + Y181C), and was more efficient than NVP in a RT inhibition assay. Besides, some measured and calculated physicochemical properties of 7d, like log P and water solubility, as well as the structure–activity relationships (SARs) analysis have been discussed in detail. Furthermore, the binding mode of the active compound 7d was rationalized by molecular simulation studies.

A series of novel piperidine-linked [1,2,4]triazolo[1,5-a]pyrimidine derivatives were synthesized and identified as inhibitors of HIV-1 wild-type and K103N + Y181C double mutant strains in this paper.Figure optionsDownload as PowerPoint slide