Proteins are able to irreversibly assemble biologically active ligands from building blocks bearing complementary reactive functions due their spatial proximity, through a kinetic target-guided synthetic process (also named in situ click chemistry). Although linkages thus formed are mostly passive, some of them have shown to significantly contribute to the protein binding through for instance hydrogen bonding and stacking interactions. Biocompatible reactions and click chemistry are a formidable source of inspiration for developing such new protein-directed ligations. This study reports a proximity-induced thiol-yne synthesis of carbonic anhydrase inhibitors. Not only this example widens the arsenal of kinetic target-guided synthesis (KTGS) eligible reactions, but the obtained product displayed unsuspected photophysical properties. The corresponding vinyl sulfide linkage conjugated to a coumarin core proved to be engaged in a monodirectional Z to E photoisomerization process. Further investigations guided by theoretical calculations showed that fine-tuning of the nature of the substituents on the coumarin moiety allows to obtain a bidirectional photochemical process, thus discovering a new photoswitching moiety, displaying moreover fluorescence properties. Due to the spectral tunability of coumarin derivatives, this work should open new opportunities for the design of vinyl sulfide-based photoswitch systems with modular photophysical properties.