Probing chelation motifs in HIV integrase inhibitors

Abstract

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 raltegravirchelator 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.

An Integrated Biological Approach to Guide the Development of Metal-Chelating Inhibitors of Influenza Virus PA Endonuclease

“…This strategy proved highly successful for creating a potent and selective HIV IN inhibitor (Agrawal et al, 2012). In the case of PA-Nter, neither of the cyclic diketo analogs tested, i.e., the indole derivatives 44-47, as well as the other DKA bioisosteres, i.e., the quinolones 25-28 and the hydroxypyrimidine carboxamide 29, had any activity in the enzymatic PA-Nter assay.…”

Inhibitors of Nucleotidyltransferase Superfamily Enzymes Suppress Herpes Simplex Virus Replication

“…Most of the inhibitors bind at the active site via interactions with the divalent cations (45)(46)(47)(48). Three anti-HIV integrase drugs have been approved by the Food and Drug Administration (FDA) (raltegravir, elvitegravir, and dolutegravir), but no anti-RNase H drugs have yet been approved.…”

Hologram quantitative structure–activity relationship and comparative molecular field analysis studies within a series of tricyclic phthalimide HIV-1 integrase inhibitors

“…As can be seen, the carbonyl-hydroxy-aromatic nitrogen motif was colored white and green, indicating neutral and positive contributions to activity, respectively, since this moiety is common for all compounds and provides a structural scaffold for holding the pharmacophoric groups in suitable orientation for maximum complementarity with the catalytic site of HIV-1 IN 9. Furthermore, the carbonyl and hydroxyl oxygens could chelate the Mg 2+ ion in the active site, an essential interaction for enzyme inhibition 9,17,18…”