Hydroxyl may not be indispensable for raltegravir: Design, synthesis and SAR Studies of raltegravir derivatives as HIV-1 inhibitors

A series of raltegravir derivatives 20–42 were prepared and systematically evaluated for their anti-HIV activity. The bioassay results showed that most of the compounds possess good to excellent anti-HIV activity. Especially, compounds 25 and 35 with subpicomole IC50 values seemed to be the most potent anti-HIV agents among all of the reported synthesized compounds. These compounds may therefore be considered as new potent anti-HIV agents. The 5-hydroxyl modification of raltegravir derivatives significantly increased the anti-HIV activity, which indicates that the hydroxyl may not be indispensable for raltegravir. The introducing of acyl at 5-position of raltegravir derivatives is favorable for antiviral activity. In addition, a high-throughput cell-based assay method with pseudotyped virus stocks was developed and used to identify HIV inhibitors.

Graphical abstractA series of raltegravir derivatives were prepared and systematically evaluated for their anti-HIV activity. The bioassay results showed that most of the compounds possess good to excellent anti-HIV activity.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► A series of raltegravir derivatives were prepared and evaluated as anti-HIV activity. ► Most of these compounds possess good to excellent anti-HIV activity. ► Compounds 25 and 35 with subpicomole IC50 values are the most potent anti-HIV agents. ► These raltegravir derivatives emerged as new potent anti-HIV agents. ► A high-throughput cell-based assay with pseudotyped virus stocks was developed.