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Substituted diarylmethylenepiperidines (DAMPs) were synthesized as conformationally restricted analogues of the alkenyldiarylmethane (ADAM) class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Although, like the ADAMs, the DAMPs were found to inhibit the cytopathic effect of HIV-1(RF) in CEM-SS cells, they were completely inactive as inhibitors of HIV-1 reverse transcriptase. The DAMPs were assessed for inhibition of HIV attachment and fusion. DAMP was active in both assays with IC(50) values of 26.5 microM (TI 3.8) and 12.1 microM (TI: >8), respectively. DAMP also inhibited HIV fusion with an IC(50 )12.8 microM (TI: >6), but not virus attachment. However, attempts to verify inhibition of virus attachment and fusion as antiviral targets using time-of-addition experiments failed to confirm these observations, and instead identified an antiviral target occurring after completion of reverse transcription. DAMPs, and were found to inhibit virus replication if added 8 h post virus exposure, and DAMP was equipotent at inhibition of virus replication if added 24 h after virus addition. DAMPs, and did not inhibit virus replication in TNF-alpha induced latently infected U1 cells, a model for post-integrative antiviral targets. When tested in both 3' end-processing and strand-transfer assays in the presence of HIV-1 integrase, none of the DAMPs showed any inhibitory activity, indicating that HIV-1 integrase is not involved in the mechanism of the antiviral action. Thus, the DAMPs are novel conformationally restricted analogues of the previously published ADAM series with an unidentified antiviral target bounded by the completion of reverse transcription and virus integration.