RESUMEN
Twenty-two pyrazoline derivatives were synthesized and tested for their human MAO (hMAO) inhibitory activity. Twelve molecules with unsubstituted ring A and substituted ring C (5-16) were found to be potent inhibitors of hMAO-A isoform with SI(MAO-A) in the order 10(3) and 10(4). Ten molecules with unsubstituted ring A and without ring C (21-30), in which eight molecules (21, 23-26, and 28-30) were selective for hMAO-A, one for hMAO-B (22) and the other one non-selective (27). Presence of ring C increases potency as well as SI towards hMAO-A; however its absence decreases both potency and SI towards hMAO-A and hMAO-B.
Asunto(s)
Inhibidores de la Monoaminooxidasa/química , Pirazoles/química , Sitios de Unión , Simulación por Computador , Humanos , Monoaminooxidasa/química , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/farmacología , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Estructura Terciaria de Proteína , Pirazoles/síntesis química , Pirazoles/farmacología , Relación Estructura-ActividadRESUMEN
Six compounds were synthesized with piperazine in linker region and hydroxamate as Zinc Binding Group (ZBG). They were screened against three cancer cell-lines (NCIH460; HCT116; U251). Compounds 5c and 5f with GI(50) value of 9.33+/-1.3 microM and 12.03+/-4 microM, respectively, were tested for their inhibitory potential on hHDAC8. Compound 5c had IC(50) of 33.67 microM. Compounds were also screened for their anticancer activity against HL60 human promyelocytic leukemia cell line due to the presence of pharmacophoric features of RR inhibitors in them. Compound 5c had IC(50) of 0.6 microM at 48h.
Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Ácidos Hidroxámicos/farmacología , Piperazinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Humanos , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/química , Modelos Moleculares , Estructura Molecular , Piperazina , Piperazinas/síntesis química , Piperazinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Ethyl and phenyl carbamate derivatives of pyrazoline (3a-3h) were synthesized and tested for their MAO inhibitory activity. All the compounds were found to be selective towards MAO-A. Phenyl carbamates (3e-3h) were better than ethyl carbamates (3a-3d) and displayed the best selectivity index. Compound 3f (KiMAO-A; 4.96 ± 0.21 nM) was found to be equally potent as that of standard drug, Moclobemide (KiMAO-A; 5.01 ± 0.13 nM) but with best selectivity index (8.86 × 10(-5)). Molecular docking studies with R &S conformer of 3f revealed S-enantiomer is better than R-enantiomer as reported earlier by other groups. It is proposed that VdW's radii of the substitution (bulkiness) in ring B determine the potency of phenyl carbamates.