RESUMEN
A library of 3,4-(methylenedioxy)aniline-derived semicarbazones was designed, synthesized, and evaluated as monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitors for the treatment of neurodegenerative diseases. Most of the new compounds selectively inhibited MAO-B and AChE, with IC50 values in the micro- or nanomolar ranges. Compound 16, 1-(2,6-dichlorobenzylidene)-4-(benzo[1,3]dioxol-5-yl)semicarbazide presented a balanced multifunctional profile of MAO-A (IC50 =4.52±0.032â µm), MAO-B (IC50 =0.059±0.002â µm), and AChE (IC50 =0.0087±0.0002â µm) inhibition without neurotoxicity. Kinetic studies revealed that compound 16 exhibits competitive and reversible inhibition against MAO-A and MAO-B, and mixed-type inhibition against AChE. Molecular docking studies further revealed insight into the possible interactions within the enzyme-inhibitor complexes. The most active compounds were found to interact with the enzymes through hydrogen bonding and hydrophobic interactions. Additionally, inâ silico molecular properties and ADME properties of the synthesized compounds were calculated to explore their drug-like characteristics.
Asunto(s)
Acetilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Diseño de Fármacos , Inhibidores de la Monoaminooxidasa/síntesis química , Monoaminooxidasa/metabolismo , Semicarbazonas/metabolismo , Acetilcolinesterasa/química , Compuestos de Anilina/química , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Concentración 50 Inhibidora , Masculino , Ratones , Simulación del Acoplamiento Molecular , Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/farmacología , Unión Proteica/efectos de los fármacos , Estructura Terciaria de Proteína , Ratas , Ratas Wistar , Semicarbazonas/síntesis química , Semicarbazonas/química , Relación Estructura-ActividadRESUMEN
Monoamine oxidase B (MAO-B) is an important drug target for the treatment of neurological disorders. A series of 6-nitrobenzothiazole-derived semicarbazones were designed, synthesized, and evaluated as inhibitors of the rat brain MAO-B isoenzyme. Most of the compounds were found to be potent inhibitors of MAO-B, with IC(50) values in the nanomolar to micromolar range. Molecular docking studies were performed with AutoDock 4.2 to deduce the affinity and binding mode of these inhibitors toward the MAO-B active site. The free energies of binding (ΔG) and inhibition constants (K(i)) of the docked compounds were calculated by the Lamarckian genetic algorithm (LGA) of AutoDockâ 4.2. Good correlations between the calculated and experimental results were obtained. 1-[(4-Chlorophenyl)(phenyl)methylene]-4-(6-nitrobenzothiazol-2-yl)semicarbazide emerged as the lead MAO-B inhibitor, with top ranking in both the experimental MAO-B assay (IC(50): 0.004±0.001 µM) and in computational docking studies (K(i): 1.08 µM). Binding mode analysis of potent inhibitors suggests that these compounds are well accommodated by the MAO-B active site through stable hydrophobic and hydrogen bonding interactions. Interestingly, the 6-nitrobenzothiazole moiety is stabilized in the substrate cavity with the aryl or diaryl residues extending up into the entrance cavity of the active site. According to our results, docking experiments could be an interesting approach for predicting the activity and binding interactions of this class of semicarbazones against MAO-B. Thus, a binding site model consisting of three essential pharmacophoric features is proposed, and this can be used for the design of future MAO-B inhibitors.