A series of HIV integrase (HIV-1 IN) inhibitors were synthesized to evaluate the 
role of the metal-binding group (MBG) in this class of metalloenzyme inhibitors. 
A total of 21 different raltegravir-chelator derivative (RCD) compounds were 
prepared that differed only in the nature of the MBG. These IN strand-transfer 
inhibitors (INSTIs) were evaluated in vitro in cell-free enzyme activity assays, 
and the in vitro results were further validated in cell culture experiments. All 
of the active compounds showed selective inhibition of the strand-transfer 
reaction over 3'-processing, suggesting a common mode of action with 
raltegravir. The results of the in vitro activity suggest that the nature of the 
MBG donor atoms, the overall MBG structure, and the specific arrangement of the 
MBG donor atom triad are essential for obtaining maximal HIV-1 IN inhibition. At 
least two compounds (RCD-4, RCD-5) containing a hydroxypyrone MBG were found to 
display superior strand-transfer inhibition when compared to an abbreviated 
analogue of raltegravir (RCD-1). By isolating and examining the role of the MBG 
in a series of INSTIs, we have identified a scaffold (hydroxypyrones) that may 
provide access to a unique class of HIV-1 IN inhibitors, and may help overcome 
rising raltegravir resistance.