scholarly journals Design, Synthesis, and Biological Evaluation of 8-Mercapto-3,7-Dihydro-1H-Purine-2,6-Diones as Potent Inhibitors of SIRT1, SIRT2, SIRT3, and SIRT5

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2755
Author(s):  
Haozhen Han ◽  
Chunpu Li ◽  
Man Li ◽  
Lisheng Yang ◽  
Sen Zhao ◽  
...  

Sirtuins (SIRT1-7) are a family of NAD+-dependent deacetylases. They regulate many physiological processes and play important roles in inflammation, diabetes, cancers, and neurodegeneration diseases. Sirtuin inhibitors have potential applications in the treatment of neurodegenerative diseases and various cancers. Herein, we identified new sirtuin inhibitors based on the scaffold of 8-mercapto-3,7-dihydro-1H-purine-2,6-dione. To elucidate the inhibitory mechanism, the binding modes of the inhibitors in SIRT3 were established by molecular docking, showing that the inhibitors occupy the acetyl lysine binding site and interact with SIRT3, mainly through hydrophobic interactions. The interactions were validated by site-directed mutagenesis of SIRT3 and structure–activity relationship analysis of the inhibitors. Consistently, enzyme kinetic assays and microscale thermophoresis showed that these compounds are competitive inhibitors to the acetyl substrate, and mix-type inhibitors to NAD+. Furthermore, we demonstrated that the compounds are potent SIRT1/2/3/5 pan-inhibitors. This study provides novel hits for developing more potent sirtuin inhibitors.

2016 ◽  
Vol 24 (12) ◽  
pp. 2707-2715 ◽  
Author(s):  
Sudha Korwar ◽  
Benjamin L. Morris ◽  
Hardik I. Parikh ◽  
Robert A. Coover ◽  
Tyler W. Doughty ◽  
...  

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5371
Author(s):  
Muhammed Çeçen ◽  
Jong Min Oh ◽  
Zeynep Özdemir ◽  
Saliha Ebru Büyüktuncel ◽  
Mehtap Uysal ◽  
...  

Twelve pyridazinones (T1–T12) containing the (2-fluorophenyl) piperazine moiety were designed, synthesized, and evaluated for monoamine oxidase (MAO) -A and -B inhibitory activities. T6 was found to be the most potent MAO-B inhibitor with an IC50 value of 0.013 µM, followed by T3 (IC50 = 0.039 µM). Inhibitory potency for MAO-B was more enhanced by meta bromo substitution (T6) than by para bromo substitution (T7). For para substitution, inhibitory potencies for MAO-B were as follows: -Cl (T3) > -N(CH3)2 (T12) > -OCH3 (T9) > Br (T7) > F (T5) > -CH3 (T11) > -H (T1). T6 and T3 efficiently inhibited MAO-A with IC50 values of 1.57 and 4.19 µM and had the highest selectivity indices (SIs) for MAO-B (120.8 and 107.4, respectively). T3 and T6 were found to be reversible and competitive inhibitors of MAO-B with Ki values of 0.014 and 0.0071, respectively. Moreover, T6 was less toxic to healthy fibroblast cells (L929) than T3. Molecular docking simulations with MAO binding sites returned higher docking scores for T6 and T3 with MAO-B than with MAO-A. These results suggest that T3 and T6 are selective, reversible, and competitive inhibitors of MAO-B and should be considered lead candidates for the treatment of neurodegenerative disorders like Alzheimer’s disease.


2012 ◽  
Vol 9 (2) ◽  
pp. 140-152 ◽  
Author(s):  
Romeo Romagnoli ◽  
Pier Giovanni Baraldi ◽  
Olga Cruz-Lopez ◽  
Maria Kimatrai Salvador ◽  
Delia Preti ◽  
...  

2013 ◽  
Vol 10 (10) ◽  
pp. 935-941
Author(s):  
Yan Tang ◽  
Zhewei Tu ◽  
Jing Sun ◽  
Xiong Zhu ◽  
Kun Liu ◽  
...  

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