DFT mechanistic study of [4+2] cycloaddition reactions of 1-methyl-1H-pyrrole-2,5-dione with furoic acid, anticancer Activity, molecular modeling and ADMET properties of new products from the Norcantharimide family substituted by a carboxylic acid

Abstract

The [4+2] cycloaddition reactions of 1-methyl-1H-pyrrole-2,5-dione, with furan-2-carboxylic acid, 5-methylfuran-2-carboxylic acid and 5 -(hydroxymethyl)-furan-2-Carboxylic acid have been studied using various theoretical approaches at the M06/6–311++G(d,p) level of theory. Conceptual DFT (CDFT) analysis shows that 1-methyl-1H-pyrrole-2,5-dione behaves as an electrophile and furan-2-carboxylic acid, 5-methylfuran-2-carboxylic acid and 5 -(hydroxymethyl)-furan-2-Carboxylic acid act as nucleophiles. Furthermore, the regioselectivity has been explored from the Parr functions and Houk's rule. The studied DA reactions followed a one-step mechanism presenting a polar character where the formation of the new bonds takes place according to an asynchronous process. The activation and reaction energy values, extracted from the energetic profile plots, allow us to determine the most favorable reaction pathway. Moreover, the topology of the electronic localization function (ELF) in specific points of the intrinsic reaction coordinate profile (IRC) associated with the most favorable reaction pathway makes it possible to highlight a non-concerted two stages one-step molecular mechanism. The valorization of the anticancer activity of six products from the Norcantharimide family substituted by carboxylic acids has been carried out using molecular docking calculations. It has been shown, for the first time, that these products are efficient against breast cancer. Finally, the physicochemical properties and medicinal potential of these products were evaluated using the SwissADME online tool, revealing that they lack toxicity and their potential as promising drug candidates.