Diketoacid chelating ligands as dual inhibitors of HIV-1 integration process

• HIV-1 Integrase is an attractive target for the development of new antivirals.
• Dual inhibitors can inhibit integration and interaction with cellular cofactors.
• Diketo acid derivatives and their Mg(II) complexes were evaluated as dual inhibitors.
• Both the complexes and the free ligands inhibit the IN-LEDGF/p75 interaction.
• Magnesium compounds showed good antiviral activity.

HIV-1 Integrase (IN) represents a very attractive pharmacological target for the development of new and more efficient drugs. Recently, an allosteric inhibitory approach also emerged, that targets the interaction between IN and cellular cofactors, such as LEDGF/p75. Small molecules based on the diketoacid pharmachophore were studied for their ability to inhibit at the same time integration and IN-LEDGF/p75 interaction (dual inhibitors): in this study, we evaluated three indole diketoacid derivatives and their magnesium(II) complexes for their ability to act as dual inhibitors.Effectively, the metal complexes exhibited IN inhibition potency in low nanomolar/micromolar concentration range; both the complexes and the free ligands are also able to inhibit the IN-LEDGF/p75 interaction at low μM values. Moreover, these magnesium compounds showed good antiviral activity, suggesting the possibility to exploit metal coordination for the design of new antivirals.

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