Structural and Electronic Determinants Underlying the Biofunctional Profile of Isothiocyanates: A Structure-activity...

Isothiocyanates (ITCs), naturally derived from glucosinolates in cruciferous vegetables, represent a versatile class of electrophilic compounds with diverse biological activities. Their characteristic -N=C=S moiety mediates covalent interactions with nucleophiles, and subtle modifications in side-chain structure critically influence their physicochemical properties, reactivity, and biological efficacy. This review aims to annotate the structure-activity relationships (SAR) of ITCs by integrating evidence from mechanistic and pharmacological studies to establish how functional group variations govern bioactivity. An extensive literature was explored, encompassing data on alkyl, aromatic, halogenated, oxidized-sulfur, and chiral ITCs, and electrophilicity index analyses. Comparative evaluation of biological assays, proteomic data, and Nrf2-Keap1 signaling studies enabled a mechanistic mapping of substituent effects. Key findings reveal that electron-withdrawing and oxidized substituents enhance electrophilicity and biological potency; conversely, chain length and lipophilicity exhibit optimal, non-linear correlations with activity. Aromatic and π-conjugated systems confer stability and sustained cellular presence, while stereochemistry contributes to enantioselective differences, as exemplified by sulforaphane enantiomers. Additionally, para-substitution and bifunctional linkers heighten activity through synergistic electronic and steric interactions. Collectively, these insights underscore that ITC bioefficacy arises from a finely balanced interplay between electronic effects and molecular geometry. The review concludes by emphasizing the translational potential of SAR-guided ITC design, covalent proteomics, and in vivo validation to accelerate the rational development of ITC-based therapeutics.