Synthesis, crystal structure, DFT calculation and confirmation of absolute configuration of empagliflozin

Abstract

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by long-term disruptions in metabolism. In the course of drug development over the past decades, sodium-glucose cotransporter 2 (SGLT2) has emerged as a novel therapeutic target for treating T2DM. Empagliflozin, a significant pharmacologically active aryl glycoside, functions as a sodium-glucose cotransporter 2 (SGLT2) inhibitor and has been extensively used for blood glucose control in patients with both T2DM and diagnosed cardiovascular disease (CVD). In this study, empagliflozin was synthesized through a six-step reaction and subjected to single-crystal growth, with its structure analyzed via X-ray diffraction. Subsequently, comprehensive computational predictions of empagliflozin's structural properties were carried out using DFT theory, encompassing infrared, nuclear magnetic resonance, Raman spectra, and ECD measurements. The results were subjected to a combined analysis with experimental data, bearing significant implications for the spectral analysis and absolute configuration determination of empagliflozin. In order to gain insights into the reasons behind the formation of empagliflozin crystals, a single crystal structure analysis was performed. Additionally, DFT calculations were employed to investigate various physicochemical properties of empagliflozin, including RDG, ELF, FMOs, MEP, etc. This study aimed to provide insights into the physicochemical properties of empagliflozin and its various non-covalent interactions. The findings are anticipated to provide valuable insights for subsequent structure optimization and drug discovery endeavors.