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 IC(50) value of 0.41 microM 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 (r(2) = 0.921; q(2) = 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.