Tracing the Reactivity and Interactions of α,β-UnsaturatedCarbonyl Acid: Insights from Experimental Charge Density Analysis

Compounds containing the α,β-unsaturated carbonyl (ketovinyl) moiety exhibit a wide range of bioactive properties, which give them a distinctive role in contemporary drug design. In this study, high-resolution X-ray diffraction analysis was employed to investigate the electron density distribution of 4-(2,4-Di-i-Pr-phenyl)-4-oxo-2-butenoic acid (DIPBA), which has demonstrated antiproliferative activity against various malignant cells in vitro. This analysis focuses on the electrostatic behavior of the ketovinyl moiety, which represents the core of reactivity and bioactivity of these kinds of Michael acceptors, enabling them to function as electrophiles that can bind to cellular thiols. The reactivity of DIPBA is presented by the structural analysis of the corresponding thio-adduct with thioglycolic acid. Because DIPBA incorporates diverse functionalities that form an extensive network of noncovalent interactions, these features are thoroughly examined through the deformation electron density, electrostatic potential, and topological analyses. The specific electrostatic properties, and the variety of noncovalent interactions in the crystal packing, suggest that this molecule can achieve selective recognition while forming stable contacts with its environment. By integrating the experimental charge density of DIPBA and the structural analysis of its thio-adduct with computational docking and molecular dynamics simulation, we trace a plausible pathway of an α,β-unsaturated carbonyl compound from the crystal to the biological environment.