Design, synthesis and structural characterization of coumarin-1,3,4-thiadiazole hybrids bearing cycloalkyl and phenyl substituents: expanding the chemical space for medicinal chemistry

The rational expansion of chemical space through molecular hybridization is a key strategy in the discovery of novel bioactive scaffolds. In this study, we report on the synthesis and structural characterization of a new series of hybrid molecules that combine coumarin and 1,3,4-thiadiazole frameworks, bearing diverse cycloalkyl and phenyl substituents at the 3-position of the coumarin ring. The synthetic route involved Knoevenagel condensation of substituted salicylaldehydes with β-ketoesters, followed by condensation with thiosemicarbazide and subsequent heterocyclization in acetic anhydride. The resulting coumarin-1,3,4-thiadiazol hybrids were obtained in good yields and fully characterized by 1H and 13C NMR spectroscopy. The integration of privileged heterocyclic motifs with varied hydrophobic fragments led to the creation of structurally diverse molecules, contributing to the expansion of chemical space relevant to medicinal chemistry and providing valuable scaffolds for future biological studies