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 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.
Dong
Ming-xin
MX
Beijing Institute of Biotechnology, Beijing 100071, PR China.
Zhang
Jian
J
Peng
Xu-qing
XQ
Lu
Hong
H
Yun
Liu-hong
LH
Jiang
Shibo
S
Dai
Qiu-yun
QY
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D055808:Drug Discovery; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation
D019380:Anti-HIV Agents; D006576:Heterocyclic Compounds, 4 or More Rings