The potential of 4-aryl-6-morpholino-3(2H)-pyridazinone-2-arylpiperazinylacetamide as a new scaffold for SIRT2 inhibition: in silico approach guided by pharmacophore mapping and molecular docking

Numerous studies have demonstrated that the aberrant enzymatic activity of SIRTs has been linked to various diseases like diabetes, cancer, inflammation, cardiovascular diseases, neurodegenerative disorders and therefore, the modulation of SIRTs is of therapeutic importance. The pharmacological action of substituted pyridazinones has been broadly studied and has received much attention on account of especially their cardiovascular, anticancer, anti-inflammatory, and analgesic activity. From this point of view, we evaluated our in-house compounds bearing substituted pyridazinone skeleton for their in vitro inhibitory potency against SIRT2 and the results were supported both by the compatibility with the pharmacophore model previously developed for selective SIRT2 inhibitors and by the interaction fingerprints in hSIRT2 active site. The results revealed that 4-aryl-6-morpholino-3(2H)-pyridazinone functionalized amide scaffold showing 48% inhibition against SIRT2 may be considered as a starting point in the development of new type SIRT2 inhibitors.