Reactivity, design and synthesis of new aryl-pyrazol-3-one derivatives of biological interest

Aryl-pyrazolones are known in scientific literature for their wide range of biological activity [1]. The occurrence of the recent approval by the U.S. FDA (Food and Drug Administration, 2017) of an aryl-pyrazol-5-one substrate such as Edaravone (Fig.1), as a novel neuroprotective agent for the treatment of ALS (Amyotrophic Lateral Sclerosis) [2], attracted us to extend research investigations on the isomeric aryl-pyrazol-3-one motif. The use of commercially available substituted reagents coupled with the easy synthetic route, optimized by us during the years, allow to obtain a wide range of suitably substituted derivatives either for biological evaluation and for exploitation as synthons. The presence of the tautomeric equilibrium, in this class of compounds, promted us to clarify some regio-selective insights, useful for developing new pyrazolone containing scaffolds. Fig.1: EdaravoneTautomeric equilibrium of 1-aryl-pyrazol-3-one Thus, we initially investigated the reactivity of the 1-(2-nitroaryl)-pyrazol-3-one moiety through nucleophilic substitution reactions carried out with different selected electrophiles and under different experimental conditions. Once assessed the different behavior of the electrophiles (R-CH2-Br) against -NH/OH tautomers, we introduced a third nucleophilic competitor on the 1-aryl moiety (R1=NH2). For this purpose, R-PhCOCl reactants were selected as electrophiles. In this way, an overview of the regioselective reactivity was obtained along with a series of new substituted(2-benzamido-aryl)-pyrazol-3-one derivatives to be biologically explored. Leave one line blank [1]El Sayed M. T., et al.Bio Med Chem Let2018, 28, 952-957. [2]Jaiswal M. K.Med Res Rev2019,39, 733-748.