Unexpected vanillin derivatives featuring a 1,3-dithiol fragment via CC bond formation: Synthetic pathways, molecular docking, ADME-Tox, molecular dynamics simulation and antimicrobial activities.

Despite numerous studies dedicated to vanillin modification, the introduction of electron-rich groups, such as the 1,3-dithiole moiety, remains underexplored. In this study, a new series of vanillin-based 1,3-dithiole derivatives (4a-e) was designed and synthesized using three distinct synthetic approaches: phosphite-promoted, Wittig, and Horner-Wadsworth-Emmons (HWE) olefination reactions. These approaches were achieved by reacting vanillin with various alkyl-substituted 1,3-dithiole fragments. These reaction conditions unexpectedly resulted in the formation of the target compounds via CC bond formation instead of the anticipated dithiafulvene (DTF) derivatives, indicating an alternative reaction pathway. The structures of the obtained compounds were unambiguously confirmed by detailed spectroscopic analyses, including 1H, 13C, FT-IR spectroscopy, and high-resolution mass spectrometry (HRMS). The in vitro antimicrobial activity of all compounds against various bacterial and fungal strains was then evaluated. Compound 4c exhibited the highest antibacterial activity (minimum inhibitory concentration = 62.5 μg/mL), while compound 4d exhibited the most potent antifungal activity. Molecular docking studies, molecular dynamics simulations, free energy landscape analysis, and pharmacokinetic and toxicological (ADME-Tox) predictions further supported these experimental results. This study highlights a novel synthetic pathway and identifies vanillin-based 1,3-dithiole derivatives as lead structures for the development of new antimicrobial agents.