Resumen: 1,4-Dihydropyridine is a privileged scaffold present in many bioactive molecules, from coenzymes to commercially available drugs. Among other interesting properties, it has been found good anticancer activity in some of these 1,4-DHPs, therefore many research groups are trying to develop new compounds based on this structural core.
For this purpose, in this work, a family of 23 new 1,4-dihydropyridines has been synthesized using hydrazide and malononitrile derivatives as precursors. This straightforward catalytic process has given rise to the desired products with moderate to excellent yields. All the compounds have been tested against four different cancer cell lines [HeLa (human cervical carcinoma), Jurkat (leukemia), A549 (human lung cancer) and MIA PaCa-2 (pancreatic cancer)] to establish a preliminary structure–activity relationship. From this study, and among the best candidates, we chose 4-chlorophenyl and 4-(trifluoromethyl)phenyl derivatives in the malononitrile ring to synthesize a second generation of molecules with enhanced cytotoxicity, modifying the substituent in the N-heterocyclic position (acylhydrazine moieties). With this second generation of compounds, we successfully decreased the IC50 until 7 µM.
An in-depth analysis of their biological properties suggests that these promising compounds trigger a non-conventional cell death mechanism known as paraptosis. Moreover, the tested photophysical properties of these products show in some cases an interesting long wavelength emission and excitation, potentially leading to new biosensors or theragnostic agents.