Pyridazinones containing dithiocarbamoyl moieties as a new class of selective MAO-B inhibitors

Abstract

Se ha diseñado y sintetizado con buen rendimiento una nueva familia de inhibidores potenciales de MAO-B que combinan dos interesantes farmacóforos, el nucleo de piridazinona y el fragmento distiocarbamato. Los resultados biológicos in vitro obtenidos con estos compuestos híbridos revelan que se comportan como inhibidores reversibles y selectivos de la isoforma B de la MAO, con valores de CI50 en el rango micromolar y que carecen de toxicidad celular. Los compuestos más interesantes de esta serie son aquellos que contienen el framento ditiocarbamato en C3 o C4 del anillo de diazina y derivatizado con una piperidina o una pirrolidina. Se realizaron estudios de modelado molecular para analizar el modo de interacción de estos compuestos con la enzima, establecer relaciones estructura actividad y predecir propiedades farmacocinéticas.

A novel class of potential MAO-B inhibitors was designed and synthesized in good yield by combining the pyridazinone moiety with the dithiocarbamate framework, two relevant pharmacophores for drug discovery. The biological results obtained for the different pyridazinone/dithiocarbamate hybrids (compounds 8–14) indicated that most of them reversibly and selectively inhibit the hMAO-B in vitro with IC50 values in the µM range and exhibit not significant cellular toxicity. The analogues 9a1, 11a1, 12a2, 12b1 and 12b2, which present the dithiocarbamate fragment derivatized with a piperidin-1-yl or pyrrolidin-1-yl group and placed at C3 or C4 of the diazine ring, were the most attractive compounds of these series. Molecular modeling studies were performed to analyze the binding mode to the enzyme and the structure activity relationships of the titled compounds, as well as to predict their drug-like properties.