Design, synthesis, and pharmacological evaluations of pyrrolo[1,2-a]quinoxaline-based derivatives as potent and selective sirt6 activators.

Sirt6 activation has emerged as a promising drug target for the treatment of various human diseases, while only limited Sirt6 activators have been reported. Herein, a series of novel pyrrolo[1,2-a]quinoxaline-based derivatives have been identified as potent and selective Sirt6 activators with low cytotoxicity. Sirt6-knockdown findings have validated the on-target effects of this class of Sirt6 activators. Docking studies indicate the protonated nitrogen on the side chain of 38 forms π-cation interactions with Trp188, further stabilizing it into this extended binding pocket. New compounds 35, 36, 38, 46, 47, and 50 strongly repressed LPS-induced proinflammatory cytokine/chemokine production, while 38 also significantly suppressed SARS-CoV-2 infection with an EC50 value of 9.3 µM. Moreover, compound 36 significantly inhibited the colony formation of cancer cells. These new molecules may serve as useful pharmacological tools or potential therapeutics against cancer, inflammation, and infectious diseases.