Design and synthesis of new isatin derivatives as HIV-1 reverse transcriptase associated ribonuclease H inhibitors

ESPOSITO, FRANCESCA;R. Meleddu;SANNA, MARIA LUISA;DISTINTO, SIMONA;CORONA, ANGELA;CANNAS, VALERIA;TRAMONTANO, ENZO;CARDIA, MARIA CRISTINA

2011-01-01

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Abstract

The human immunodeficiency virus (HIV) is the etiological agent of the acquired immunodeficiency syndrome (AIDS) in humans. Despite the fact that many therapeutic agents targeted to the viral reverse transcriptase (RT), the multifunctional enzyme which is responsible for the viral genome replication, are already clinically available, none of them is active on the RT-associated Ribonuclease H (RNase H) activity, whose function is essential for viral replication and, hence, is an attractive target for drug development. In the last few years, a few classes of compounds have been identified as HIV-1 RNase H inhibitors, however, none of them was able to reach clinical trial testing. Thus, efforts in the development of new compounds targeting the RNase H activity are relevant to enhance the antiretroviral armamentarium and constitute an attractive challenge for medicinal chemists. In this perspective, within an RNase H drug discovery program, we designed and synthesized a series of differently substituted isatin derivatives and tested them on both HIV-1 RT-associated RNase H and DNA polymerase functions. Within these compounds, isatin derivatives appeared as promising scaffold for the inhibition of the HIV-1 RT-associated RNase H activity. The resulting SAR study may provide significant hints for the determination of the pharmacophoric requirements for the interaction with this viral target