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

Abstract

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.

Discovery of the Diphenyl 6-Oxo-1,6-dihydropyridazine-3-carboxylate/carboxamide Analogue J27 for the Treatment of Acute Lung Injury and Sepsis by Targeting JNK2 and Inhibiting the JNK2-NF-κB/MAPK Pathway

“…Dihydrozinone is a broad-spectrum pharmacophore, and dihydrozinone derivatives have been shown to exert long-lasting anti-inflammatory effects on LPS-induced foot edema and air sacs in mice by regulating the release of IL-6 and TNF-α . Dubey et al also reported on the use of compounds with these structures ( B1 , B2 ) in inflammation .…”

2‐(Methyl(phenyl)amino)‐N‐(phenyloxyphenyl)acetamide structural motif representing a framework for selective SIRT2 inhibition

“…As a consequence, abnormal expression of SIRT2 is widely believed to be closely related to diverse diseases, such as neurological and metabolic disorders and cancer (Kaya & Eren, 2024;Zhang et al, 2020). Meanwhile, the potential of SIRT2 as a promising intervention has driven researchers to develop SIRT2 inhibitors (Abbotto et al, 2023;Cai et al, 2023;Eren et al, 2019;Gozelle et al, 2022Gozelle et al, , 2023Mellini et al, 2017;Quinti et al, 2016;Rumpf et al, 2015;Spiegelman et al, 2019;Sukuroglu et al, 2021;Tantawy et al, 2021;Trapp et al, 2006;Yagci et al, 2021;Yang et al, 2018Yang et al, , 2019Yang et al, , 2020, most of which have poor isoform selectivity or cellular potency (Kudo et al, 2018).…”