(3Z)-3-(2-[4-(aryl)-1,3-thiazol-2-yl]hydrazin-1-ylidene)-2,3-dihydro-1H-indol-2-one derivatives as dual inhibitors of HIV-1 reverse transcriptase

• A series of indolinones derivatives has been synthesized and characterised.
• The compounds showed to be HIV 1 RT dual inhibitors in the low micromolar range.
• A protocol to investigate the mode of action has been devised.
• Compounds do not bind Mg++ ions in the RNase H catalytic site.
• Activity is not affected by common NNRTIBP RT mutations.

The HIV-1 Reverse Transcriptase (RT) is a validated and deeply explored biological target for the treatment of AIDS. However, only drugs targeting the RT-associated DNA polymerase (DP) function have been approved for clinical use. We designed and synthesised a new generation of HIV-1 RT inhibitors, based on the (3Z)-3-(2-[4-(aryl)-1,3-thiazol-2-yl]hydrazin-1-ylidene)-2,3-dihydro-1H-indol-2-one scaffold. These compounds are active towards both RT-associated functions, DNA polymerase and ribonuclease H. The structure, biological activity and mode of action of the new derivatives have been investigated. In particular, the nature of the aromatic group in the position 4 of the thiazole ring plays a key role in the modulation of the activity towards the two RT-associated functions.

The synthesis of indolinone derivatives based on a previously identified analogue led to the confirmation of this scaffold as a promising hit for the design of dual inhibitors of the two reverse transcriptase associated functions, DNA polymerase and ribonuclease H (RNase H) activities.Figure optionsDownload as PowerPoint slide