Cl with OMe (1 and 3) in good yields. For the phenyltriazolyl-2-amino-4-pyrimidinone analogs (series (3) click chemistry was performed be1phenyltriazolyl-2-amino-4-pyrimidinone series, the appears more favorable than m-NO2 and 3, a phenyl ring substitution with m-COOH two). (1). Finally, the 6-chloro 2,4-diamino distinct pyrimidinones connected to an alkyne motif tween several aromatic azides and pyrimidine compound 2 substituted with m-COOMe 1st, with 1 carbon lengths displays reasonably poor inhibition. (Figure 4B). The corresponding and 2,6-diamino-4via linkersthe diazonium coupling between substituted anilines analogs (64) were chloropyrimidine or yields. changes in linker length and phenyl ring substitution affect In series 2, generally, obtained in 438 2,four,6-triaminopyrimidine yielded the corresponding analogs (I, two, four, and five) inhibitoryHPPK inhibition yields. broadly nucleophilic aromatic substitution10)The HPPK in moderate to excellent varies Next, based on with one- substituents. or In series 1, activity of your compounds. For compounds R and R’ (6, 7, 8, 9, with MeOH mediated and 14) linker the replacement of Cl with OMe triazole rings (R group), three-carbon (13is obtained for involving the pyrimidinone bearing and substituentyields. best inhibition by NaH led to the triamino pyrimidine four and (1 no three) in good on the For the phenyltriazolyl-2-amino-4-pyrimidinone with p-COOH. Altering of R” from substitution with m-COOH is more favorable than series, the click chemistry was methyl to ethyl additional increases the enzyme inhibitory activity. Among these compounds,Molecules 2022, 27,1 and 3, a phenyl ring substitution with m-COOH (3) appears much more favorable than m-NO2 (1). Ultimately, the 6-chloro two,4-diamino pyrimidine compound 2 substituted with m-COOMe displays reasonably poor inhibition. In series 2, normally, modifications in linker length and phenyl ring substitution affect HPPK inhibitory activity with the compounds. For compounds with one- (6, 7, eight, 9, ten) or 7 of 18 three-carbon (13 and 14) linker involving the pyrimidinone and triazole rings (R group), substitution with m-COOH is far more favorable than with p-COOH. Changing of R” from methyl to ethyl further increases the enzyme inhibitory activity. Among these compounds,3-carbon3-carbon linker, m-COOHEt (R”) is Et (R”) is active, with 42.8 inhibition 14 with 14 with linker, m-COOH (R’) and (R’) along with the most by far the most active, with 42.8 at 1 mM. Interestingly, in case of 2-carbon linker, p-COOH (11) is (11) favorable than inhibition at 1 mM. Interestingly, in case of 2-carbon linker, p-COOHmoreis far more favoram-COOH (12). ble than m-COOH (12). For probably the most potent compounds in every series, dose-response inhibition experiment For probably the most potent compounds in each series, aadose-response inhibition experiment was carried out Compound was conducted to establish IC50 values against the enzyme.IGFBP-3 Protein supplier Compound 14 showed IC50 50 50 values against the of 814 47 M, when IC50 could not be determined for 44due to limited solubility at higher 814 47 , while IC50 could not be determined for as a result of limited solubility at high of concentrations (Figure S5).CA125 Protein medchemexpress concentrations (Figure S5).PMID:35901518 two.four. Molecular Docking 2.four. Molecular Docking To insights in to the mode of of binding the active compounds, all structures have been To acquire obtain insights into the modebinding of on the active compounds, all structureswere studied by molecular docking making use of the higher precision mode of Maestro software program, in order studied by molecular dockin.