Tricyclononene carboxamide derivatives as novel anti-HIV-1 agents

By modifying the chemical structure of anti-orthopoxvirus compound ST-246, we designed and synthesized a series of tricyclononene carboxamide derivatives and tested their anti-HIV-1 activity and cytotoxicity. We found that benzoimidazol-containing compound 7g was highly effective in inhibiting HIV-1 R5 infection with an IC50 value of 0.41 μM and a selectivity index of 292, but it exhibited no significant inhibitory activity on HIV-1 reverse transcriptase, integrase and protease. CoMFA was used to analyze structure–activity relationships with good predictive power (r2 = 0.921; q2 = 0.582). Moreover, the CoMFA model showed that the length of the molecule, the amide, and the amine moieties all played crucial roles in anti-HIV activity. These results suggest that 7g may serve as a lead for the development of novel anti-HIV-1 therapies.

Graphical abstractA series of tricyclononene carboxamide derivatives based on anti-orthopoxvirus compound ST-246 were synthesized and characterized as novel anti-HIV-1 agents.Figure optionsDownload full-size imageDownload as PowerPoint slide