A series of novel piperine–resveratrol hybrids 5a–h was designed, synthesized, and structurally elucidated
by IR, and 1H, 13C, and 19F NMR. Antiproliferative activities of 5a–h were evaluated by NCI against sixty
cancer cell lines. Compound 5b, possessing resveratrol pharmacophoric phenolic moieties, showed
a complete cell death against leukemia HL-60 (TB) and Breast cancer MDA-MB-468 with growth
inhibition percentage of 0.49 and 2.83, respectively. In addition, 5b recorded significant activity
against the other cancer cell lines with growth inhibition percentage between 80 to 95. New 5a–h
hybrids were evaluated for their inhibitory activities against Sirt-1 and Sirt-2 as molecular targets for their
antiproliferative action. Results showed that compounds 5a–h were more potent inhibitors of Sirt-2 than
Sirt-1 at 5 mm and 50 mm. Compound 5b showed the strongest inhibition of Sirt-2 (78 3% and 26 3%
inhibition at 50 mM and 5 mM, respectively). Investigation of intermolecular interaction via Hirschfeld
surface analysis indicates that these close contacts are mainly ascribed to the O–H/O hydrogen
bonding. To get insights into the Sirt-2 inhibitory mechanism, a docking study was performed where 5b
was found to fit nicely inside both extended C-pocket and selectivity pocket and could compete with
the substrate acyl-Lys. Another possible binding pattern showed that 5b could act by partial occlusion of
the NAD+ C-pocket. Collectively, these findings would contribute significantly to better understanding
the Sirt-2 inhibitory mechanism in order to develop a new generation of refined and selective Sirt-2
inhibitors.