The indole heterocyclic motif is commonly found in pharmaceutical molecules, and its derivatives have attracted considerable attention due to important biological activities. During the course of evaluating the biologic potential of a commercial compound library, 2-phenylindole was identified as an inhibitor of nitrite production. Nitric oxide (NO) is formed by nitric oxide synthase (NOS) from L-arginine and is an important cellular signaling molecule. Overproduction of NO can lead to inflammation and cancer. As such, we have undertaken systematic chemical optimization based on this indole lead molecule to develop novel NOS inhibitors. Using one-pot palladium catalyzed Sonogashira-type alkynylation and base-assisted cycloaddition, we synthesized a chemically diversified indole library from an array of substituted 2-iodoanilines and terminal alkynes. Subsequent biological evaluation revealed several of the derivatives (e.g., 3-carboxaldehyde oxime and cyano substituted 2-phenylindoles; IC50 values of 4.4�0.5 and 4.8�0.4 �M, respectively) demonstrated improved inhibition in NO production relative to 2-phenylindole (IC50 = 38.1�1.8 �?). Synthesis and structure-activity relationship of this novel class of NOS inhibitors will be discussed, as well as their regulation of NF?B.

Discovery and design of 2-phenylindole-based nitric oxide synthesis inhibitors as potential antiinflammatory and chemopreventive agents

243rd National Meeting (2012)

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