Neuroactive alkaloids from Psychotria (Rubiaceae) are SIRT inhibitors

Epigenetic enzymes such as histone deacetylases (HDACs) play a crucial role in the development of aging-related diseases. Among human HDAC isoforms, class III HDACs, also known as sirtuins (SIRTs), have been considered as promising targets for treating neurodegenerative conditions [1]. Psychotria alkaloids have been reported for their inhibitory properties against central nervous system (CNS) cholinesterases and monoamine oxidases [2]. Given the multifunctional profile of these alkaloids in the CNS, we hypothesized that they could also interact with SIRTs. Here, we show the SIRT inhibition by alkaloids previously isolated from Psychotria spp. first by in silico methods, followed by enzymatic and cell assays. Five alkaloids, namely, vallesiachotamine lactone, E-vallesiachotamine, Z-vallesiachotamine, prunifoleine, and 14-oxoprunifoleine showed an inhibitory profile comparable to that of sirtinol, used as reference compound, in a dose response manner from 10 to 150 µM (Figure 1). The cytotoxicity on rat astrocytes and human cells was also evaluated and correlated to the pharmacokinetic profile of tested compounds.