A rapid synthesis of 5-substituted 7-amino-6-cyano-1,5-dihydro-1H-pyrano[2,3-d]pyrimidine-2,4(3H)-diones and their in silico / evaluation against SIRT1

Discovery of Novel N-Acylhydrazone Derivatives as Potent Inhibitors of Sirtuin-1

“…The same set of the active pocket residues of SIRT1 has been identified for binding recognition of other structurally diverse inhibitors. 28,46,47 Ligands 3a and 3b revealed high binding affinity from -9.5 to -9.6 kcal/mol towards the SIRT1/NAD + receptor, which is of the same magnitude as the best-binding known inhibitors, such as Selermide and Sirtinol (see the Supporting Information, Figure S01). In terms of binding affinity, these ligands are better alternatives to other known inhibitors, such as Tenovin-1 and Tenovin-6 (Figure 3), as seen in Table 1.…”

“…Due to the well-characterized structure, the catalytic domain of SIRT1 has been used as a target receptor for in silico screening of binding parameters of SIRT1 modulators. [44][45][46][47][48][49][50]58,[61][62][63] To test whether our molecular docking approach is able to reproduce properly the correct binding mode of the cocrystallized inhibitor Ex527, we first re-docked it against the corresponding crystal structure of SIRT1 (PDB 4I5I). 58 It has been suggested that the presence of the co-factor NAD + was essential for the activity of the SIRT1 enzyme 45 so it was maintained in the binding site for the docking study.…”

“…25 Over the past years, different SIRT inhibitors have been found among various classes of compounds. 7,[26][27][28][29][30][31][32] Downregulating activity towards HDACs class III was identified in 2-anilinobenzamides (nicotinamide analogues), 33 some acetyl lysine mimics, 26 azomethines based on 2-hydroxy-1naphthaldehyde (sirtinol, JGB1714 and others analogues), 34,35 thioureas (cambinol, tenovin-6), 36,37 and thiobarbituric acid 5-ylidene derivatives, 38 bis(indolyl)maleinimides, 34 5-benzylidene-2-phenyl-1,3-dioxane-4,6-diones 39 and indole derivatives, 40,41 naphtho[2,1-b]pyrane-3ones (splitomicin and analogues), 42 thieno[3,2-d]pyrimidine-6-carboxamides, 43 2-substituted nicotinic acid ethyl esters, 44 dihydro-1,4-benzoxazine carboxamides, 45 1,5-dihydro-1H-pyrano[2,3-d]pyrimidine-2,4(3H)-diones, 46 dihydropyrano[2,3-c]pyrazole, 47 2-arylamino-3-cyanopyridines, 48 3-heteroarylmethylene isoindolin-1-ones, 49 1,8-dioxo-octahydroxanthenes, 50 highly ionized naphthylurea suramin, 51 and various substances from natural sources (amurensin G) 52 or modified natural products such as steroids. 35 Most of these compounds have been evaluated using enzymatic and cell-based assays.…”

Recent developments using malononitrile in ultrasound-assisted multicomponent synthesis of heterocycles

“…The most potent compound among all those tested, 7-amino-5-(3-bromophenyl)-2,4-dioxo-1,3,4,5-tetrahydro-2 H -pyrano[2,3- d ]pyrimidine-6-carbonitrile, was several times more potent than nicotinamide based on SIRT1 IC 50 values. The in-silico assessment also predicted that it would have favorable pharmacokinetic properties in MCF7 and HEK 293 T cells [102] .…”

Recent Advances in the Discovery of SIRT1/2 Inhibitors via Computational Methods: A Perspective

“…Tripeptide linked to heterocyclic nuclei [117] Furopyridine derivatives [118] Indole compounds (strictly related to EX-527) [119] Benzylidene-dioxane compounds [120] Pyridine derivatives [121,122] Tryptophan conjugates [77] Pyrano [2,3-d ]pyrimidinone derivatives [123] Variable five-membered ring derivatives [81] Thienopyrimidone derivatives [74] 1,8-dioxo-octahydroxanthene derivatives [76]…”