Development of Electrochemical Cyclization Reactions of Aryl Azides and Synthesis of NAMPT Activators

High throughput screening (HTS) identified NAMPT positive allosteric modulators (N-PAMS) whose binding with NAMPT was confirmed through a cocrystal structure. Analogs of the initial hit N-PAMs were synthesized to increase NAMPT activity in human THP-1 monocyte cells. Promising analogs were evaluated in neuronal HT-22 mouse hippocampal cell line subjected to inflammatory stress using tumor necrosis factor alpha (TNFα) to determine their effectiveness in reducing reactive oxygen species. These screens revealed an N-PAM that completely reduced ROS elevation in THFα glutamate-stressed HT-22 cells, a model of neuronal excitotoxicity. A study into the amination of C–H bonds through electrochemical oxidation was performed to access N-aryl nitrenoid formation from aryl amines. Anodic oxidation provides the potential to access reactive intermediates without chemical oxidant. Reaction conditions were screened using an undivided cell in an IKA electrasyn 2.0. Anodic oxidation of aryl amines to afford 3H-indoles proved to be a success. The reaction conditions were broad and tolerated electronic and steric changes. Further examination into diastereoselectivity indicated that electronic changes to π-π interactions play a role in diastereoselectivity of the reaction. Access to 3H-indoles was pursued through anodic oxidation of aryl azides was additionally investigated. Optimization of the electrochemical conditions provided a great conversion of aryl azide to 3H-indoles. This work provides the basis for future studies into the scope and mechanism of this reaction.