Identification of Novel N-(Aryl)-3-(N-benzylsulfamoyl)benzamides as NAMPT Activators

Nicotinamide adenine dinucleotide (NAD⁺) plays a central role in numerous physiological processes, and maintaining or increasing cellular NAD⁺ levels has emerged as a promising strategy for promoting healthy aging. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD+ salvage pathway, which makes it an attractive target for the treatment of many diseases associated with NAD+ depletion, such as inflammation, neurodegenerative, and metabolic diseases. Herein, we report the synthesis and in vitro biological evaluation of STA1-STA3, which increased NAMPT activation by 2- to 38-fold. In addition, molecular docking studies were conducted within both the catalytic and allosteric sites of NAMPT, and the resulting binding patterns were analyzed to correlate structural differences with the observed in vitro NAMPT activity, highlighting the significance of molecular interactions.