Preparation of 2-Nitrocacalol Acetate From a Sesquiterpene Isolated From Roots of Psacalium decompositum. Evaluation of α-Glucosidase and Acetylcholinesterase Inhibition

Abstract

Objective To introduce a nitrogen atom into the structure of the cacalol acetate and to evaluate the change in its ability to inhibit enzymes of therapeutic importance such as α-glucosidase and acetylcholinesterase (AChE), which are targeted in the development of drugs for the treatment of diabetes and Alzheimer’s disease (AD), respectively. Methods Cacalol acetate was obtained by subjecting the hexane and ethyl acetate extracts from the roots of Psacalium decompositum to acetylation conditions. Subsequently, the cacalol acetate was brought under nitration conditions using cerium (IV) ammonium nitrate and acetic anhydride to obtain 2-nitrocacalol acetate; this compound was characterized by nuclear magnetic resonance, mass spectrometry, and X-ray diffraction techniques. Additionally, the inhibitory activity of the ethyl acetate extract, the cacalol acetate, and the 2-nitrocacalol acetate was evaluated on the enzymes α-glucosidase and AChE. Finally, the possible mode of ligand–enzyme binding through molecular docking was established. Results The 2-nitrocacalol acetate was obtained with a 20% yield. Its crystallographic structure was obtained, to our knowledge, for the first time, corroborating the S configuration in C5, showing a mostly planar molecule, in which the C6, C7, and C14 atoms and the acetyl group leaving the plane. The ethyl acetate extract was that which significantly inhibited the α-glucosidase (95.8% at 100 μg/mL), while the 2-nitrocacalol acetate exhibited the highest inhibitory activity of the AChE (69.9% at 10 µg/mL). The 2-nitrocacalol acetate presented a favorable interaction energy with the AChE (−8.68 kcal/mol), highlighting the formation of two hydrogen bonds and hydrophobic interactions. Conclusions The 2-nitrocacalol acetate and its crystallographic structure were obtained, to our knowledge, for the first time providing a new modification to this sesquiterpene by introducing a nitro group, which was favored its ability to inhibit AChE. These structural modifications encourage future research in these sesquiterpenes as targets for the development of novel drugs that would be useful in clinical practice.