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

ABSTRACT: 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.

SUBMITTER: Xu J 

PROVIDER: S-EPMC9805530 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature