Synthesis of C3,C6-Diaryl 7-Azaindoles via One-Pot Suzuki-Miyaura Cross-Coupling Reaction and Evaluation of Their HIV-1 Integrase Inhibitory Activity

There is a continuing demand of new inhibitors of HIV-1 Integrase (HIV-1 IN) due to mutations of HIV-1. This study aims to develop the synthesis of 3,6-diaryl 7-azaindoles and introspect the role of aryl groups on the strand transfer (ST) inhibition of HIV-1 IN. An efficient and chemo-selective one-pot method is established for the synthesis of the unexplored diverse C3 -> C6 diaryl 7-azaindoles starting from 6-chloro-3-iodo-N-protected 7-azaindoles. Here we report Pd2dba3/SPhos catalyzed synthesis of eight selective C3 monoaryl 7-azaindoles (10a-h) and eight C3,C6-diaryl 7-azaindoles (11a-f, 12a,b) with yields in the ranges of 67-93% and 43-88% respectively. The synthesized derivatives inhibit the strand transfer (ST) activity of HIV-1 IN enzyme at 10 mu M dose with 11d and 11f exhibiting %ST inhibitions of 72% and 71%, respectively. SAR studies indicate the para-substitution on the C3 aryl ring and C6 aryl is essential for enhanced %ST inhibition. 11b,c, 11e-f, and 12b showed lower cytotoxicity (IC50 > 200 mu M) against TZM-bl cells. Molecular docking of the diaryl 7-azaindoles and Raltegravir (RAL), to the PFV-integrase revealed favorable binding interactions.

Automated summary

There is a continuous demand for new inhibitors of HIV-1 Integrase (HIV-1 IN) due to HIV-1 mutations. This study developed an efficient and chemo-selective method for synthesizing diverse C3 -> C6 diaryl 7-azaindoles that inhibit the strand transfer (ST) activity of HIV-1 IN enzyme. The synthesized compounds exhibited significant %ST inhibition, with para-substitution on the C3 aryl ring and C6 aryl being essential for enhanced %ST inhibition.