Isatin derivatives as new scaffolds for HIV-1 reverse transcriptase associated RNase H and RDDP dual inhibitors

Background. Many AIDS therapeutic agents are targeted to the human immunodeficiency virus (HIV) reverse transcriptase (RT), the multifunctional enzyme which is responsible for the viral genome replication. The HIV-1 RT has two enzymatic associated functions, DNA polymerase and ribonuclease H (RNase H), both essential for genome reverse transcription and, therefore, both attractive targets for drug development. Currently, none of the approved antiviral agents is active on both functions. Hence, the identification of new scaffolds capable to achieve the inhibition of both enzymatic functions is an innovative approach which may reduce the selection of mutant viruses, resistant to single target drugs, and is an attractive challenge for medicinal chemists and virologists. Methods. We designed and synthesized a series of differently substituted isatin derivatives and tested them on the HIV-1 RT-associated RNase H and DNA polymerase functions and viral replication. Results. The isatin derivatives inhibited both HIV-1 RT-associated functions in the low micromolar range and they were assessed also on the Y181C and K103N mutant RTs. Mechanism of action studies showed that they do not chelate the divalent ion cofactor and do not interact with the HIV-1 RNase H active site. Conclusions. The newly synthesized isatin derivatives are a promising scaffold for HIV-1 RT dual inhibitors. They probably bind to an allosteric site without interacting with the HIV-1 RNase H active site. The obtained SAR study will provide significant hints for the determination of the pharmacophoric requirements for the interaction with the viral target and will give new information for hit optimization.