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1.
Bioorg Chem ; 107: 104524, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33317836

RESUMO

The synthesized Schiff Bases were reacted with formaldehyde and secondary amine such as 2,6-dimethylmorpholine to afford N-Mannich bases through the Mannich reaction. 3-Substitued-4-(4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones (4) were treated with 2,6-dimethylmorpholine in the presence of formaldehyde to synthesize eight new 1-(2,6-dimethylmorpholino-4-yl-methyl)-3-substitued-4-(4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones (4a-h). The structures of the synthesized eight new compounds were characterized using IR, 1H NMR, 13C NMR, and HR-MS spectroscopic methods. Synthesized compounds inhibitory activity determined against the acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and glutathione S-transferase (GST) enzymes with Ki values in the range 25.23-42.19 µM for AChE, 19.37-34.22 µM for BChE, and 21.84-41.14 µM for GST, respectively. Binding scores of most active inhibitors against AChE, BChE, and GST enzymes were detected as -10.294 kcal/mol, -9.562 kcal/mol, and -7.112 kcal/mol, respectively. The hydroxybenzylidene moiety of the most active inhibitors caused to inhibition of the enzymes through hydrophobic interaction and hydrogen bond.


Assuntos
Inibidores da Colinesterase/farmacologia , Bases de Mannich/farmacologia , Morfolinas/farmacologia , Bases de Schiff/farmacologia , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Células CACO-2 , Domínio Catalítico , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Cães , Desenho de Fármacos , Ensaios Enzimáticos , Glutationa Transferase/antagonistas & inibidores , Glutationa Transferase/química , Glutationa Transferase/metabolismo , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Células Madin Darby de Rim Canino , Bases de Mannich/síntese química , Bases de Mannich/metabolismo , Simulação de Acoplamento Molecular , Morfolinas/síntese química , Morfolinas/metabolismo , Ligação Proteica , Bases de Schiff/síntese química , Bases de Schiff/metabolismo
2.
Chem Biodivers ; 18(12): e2100433, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34596972

RESUMO

In the present study, 3-substitued-4-(4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones (S1-8) were synthesized by treating 4-hydroxybenzaldehyde (B) with eight different 3-substitued-4-amino-4,5-dihydro-1H-1,2,4-triazole-5-ones (T1-8) in acetic acid medium, separately. The synthesized Schiff bases (S) were reacted with formaldehyde and secondary amine such as 4-piperidinecarboxyamide to afford novel heterocyclic bases. 3-Substitued-4-(4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones (T) were treated with 4-piperidinecarboxyamide in the presence of formaldehyde to synthesize eight new 1-(4-piperidinecarboxyamide-1-yl-methyl)-3-substitued-4-(4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones (M1-8). The structure characterization of compounds was carried out using 1 H-NMR, IR, HR-MS, and 13 C-NMR spectroscopic methods. The inhibitory properties of the newly synthesized compounds were calculated against the acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and glutathione S-transferase (GST) enzymes. Ki values were calculated in the range of 20.06±3.11-36.86±6.17 µM for GST, 17.87±2.91-30.53±4.25 µM for AChE, 9.08±0.69-20.02±2.88 µM for BChE, respectively, Besides, IC50 values were also calculated. Best binding scores of -inhibitors against used enzymes were calculated as -12.095 kcal/mol, -12.775 kcal/mol, and -9.336 kcal/mol, respectively. While 5-oxo-triazole piperidine-4-carboxamide moieties have a critical role in the inhibition of AChE and GST enzymes, hydroxy benzyl moiety is important for BChE enzyme inhibition.


Assuntos
Inibidores Enzimáticos/farmacologia , Glutationa Transferase/antagonistas & inibidores , Compostos Heterocíclicos/farmacologia , Piperidinas/farmacologia , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Glutationa Transferase/metabolismo , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Bases de Schiff/síntese química , Bases de Schiff/química , Bases de Schiff/farmacologia , Espectrofotometria Infravermelho
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