Coumarin Compounds with 6- or 7-(4-Aminobutynyloxy) Substituent: Synthesis, In Vitro Cytotoxicity and In Silico DNA Binding Studies.

Coumarin compounds are of great interest in drug development research. Various substituents on the coumarin core significantly influence its biological activity. Although a number of coumarins with specific biological properties have already been identified, the ongoing challenge lies in the design and synthesis of novel derivatives with high specificity for pharmacological targets. In this work, 6-(4-aminobut-2-ynyloxy)- and 7-(4-aminobut-2-ynyloxy)-substituted coumarin derivatives were designed and synthesized. As a method for the synthesis of 6- or 7-substituted coumarins (yields 26-98%), a copper-catalyzed one-pot three-component reaction (A3 coupling) of 6- or 7-(prop-2-ynyloxy)coumarins with formaldehyde and secondary amines was studied. In vitro biological testing (MTT assay) results showed that the new coumarins exhibit pronounced cytotoxicity against human cervical cancer (C33 A and CaSki) and breast cancer (MCF-7) cell lines, with activity being dependent on the substituent at the nitrogen atom in the side chain. The most active compounds inhibited tumor cell growth, with GI50 values of 4.3-9.4 μM (SI = 9.1-19.8). All new compounds demonstrated low cytotoxicity against the non-malignant epithelial VERO cells (GI50 > 86 μM). To understand the observed SAR trends, molecular modeling of the interaction between the new coumarin derivatives and DNA G-quadruplex binding sites was performed.