Identification of Aristolactam Derivatives That Act as Inhibitors of Human Immunodeficiency Virus Type 1 Infection and Replication by Targeting Tat-Mediated Viral Transcription

Despite the success of antiretroviral therapy(ART),efforts to develop new classes of antiviral agents have been hampered by the emergence of drug resistance.Dibenzo-indole-bearing aristolactams are compounds that have been isolated from various plants species and which show several clinically relevant effects,including anti-inflammatory,antiplatelet,and antimycobacterial actions.However,the effect of these compounds on human immunodeficiency virus type 1(HIV-1)infection has not yet been studied.In this study,we discovered an aristolactam derivative bearing dibenzo[cd,f]indol-4(5 H)-one that had a potent anti-HIV-1 effect.A structure-activity relationship(SAR)study using nine synthetic derivatives of aristolactam identified the differing effects of residue substitutions on the inhibition of HIV-1 infection and cell viability.Among the compounds tested,1,2,8,9-tetramethoxy-5-(2-(piperidin-1-yl)ethyl)-dibenzo[cd,f]indol-4(5 H)-one(Compound 2)exhibited the most potent activity by inhibiting HIV-1 infection with a half-maximal inhibitory concentration(IC50)of 1.03 lmol/L and a half-maximal cytotoxic concentration(CC50)of 16.91 lmol/L(selectivity index,16.45).The inhibitory effect of the compounds on HIV-1 infection was linked to inhibition of the viral replication cycle.Mode-of-action studies showed that the aristolactam derivatives did not affect reverse transcription or integration;instead,they specifically inhibited Tat-mediated viral transcription.Taken together,these findings show that several aristolactam derivatives impaired HIV-1 infection by inhibiting the activity of Tat-mediated viral transcription,and suggest that these derivatives could be antiviral drug candidates.