Synthesis and Structural Characterization of Substituted 4-Alkynyloxazolones: In Silico Insights on the Interaction with SARS-CoV-2 Spike Glycoprotein

Research on oxazolones, particularly 4-alkynyloxazolones, has garnered increasing interest due to the presence of an alkynyl group, which facilitates molecular conjugation and enables diverse chemical modifications. In this study, three representative 4-alkynyloxazolone derivatives (L1–L3) were synthesized and structurally characterized through single-crystal X-ray diffraction and computational analysis to obtain a reliable structure of L1–L3 to subsequently predict in silico interactions with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein. The crystallographic results revealed high molecular planarity and multifurcated hydrogen bonding. Considering the obtained crystallographic structure, theoretical descriptors such as HOMO–LUMO energy gaps and electrostatic potential maps indicated that these compounds exhibit favorable electronic reactivity, particularly for L3, with favorable drug-like predictions. The lack of methoxy groups in L2 and L3 makes these compounds have lower predicted toxicity parameters than L1. Molecular docking calculations targeting SARS-CoV-2 spike glycoprotein in three different feasible conformations in a biological matrix, i.e., three receptor-binding domains (RBD) in down conformation, two RBD in down and one in up conformation, as well as RBD bound to the human receptor angiotensin-converting enzyme 2 (ACE2), suggested strong binding affinities and specific interactions with the RBD moiety, mainly in the up conformation. Overall, this work integrates crystallographic and computational approaches to establish the structural and in silico evaluation of spike-binding properties of early substituted 4-alkynyloxazolones, suggesting L3 as a candidate for future in vitro antiviral assays.