Synthesis of 2-arylindole derivatives and evaluation as nitric oxide synthase and NFκB inhibitors

Development of small molecule drug-like inhibitors blocking both nitric oxide synthase and NF kappa B could offer a synergistic therapeutic approach in the prevention and treatment of inflammation and cancer. During the course of evaluating the biological potential of a commercial compound library, 2-phenylindole (1) displayed inhibitory activity against nitrite production and NF kappa B with IC50 values of 38.1 +/- 1.8 and 25.4 +/- 2.1 mu M, respectively. Based on this lead, synthesis and systematic optimization have been undertaken in an effort to find novel and more potent nitric oxide synthase and NF kappa B inhibitors with antiinflammatory and cancer preventive potential. First, chemical derivatizations of 1 and 2-phenylindole-3-carboxaldehyde (4) were performed to generate a panel of N-alkylated indoles and 3-oxime derivatives 2-7. Second, a series of diversified 2-arylindole derivatives (10) were synthesized from an array of substituted 2-iodoanilines (8) and terminal alkynes (9) by applying a one-pot palladium catalyzed Sonogashira-type alkynylation and base-assisted cycloaddition. Subsequent biological evaluations revealed 3-carboxaldehyde oxime and cyano substituted 2-phenylindoles 5 and 7 exhibited the strongest nitrite inhibitory activities (IC50 = 4.4 +/- 0.5 and 4.8 +/- 0.4 mu M, respectively); as well as NF kappa B inhibition (IC50 = 6.9 +/- 0.8 and 8.5 +/- 2.0 mu M, respectively). In addition, the 6'-MeO-naphthalen-2'-yl indole derivative 10at displayed excellent inhibitory activity against NF kappa B with an IC50 value of 0.6 +/- 0.2 mu M.