Design, synthesis, biological and in silico evaluation of 3‑carboxy‑coumarin sulfonamides as potential antiproliferative agents targeting HDAC6.

Breast cancer (BC) is the most common cancer and the main cause of mortality due to cancer in women around the World. Histone deacetylase 6 (HDAC6) is a promising target for the treatment of BC. In the present study, a series of novel 3-carboxy-coumarin sulfonamides, analogs of belinostat, targeting HDAC6 were designed and synthesized. The compounds were synthesized and purified through open-column chromatography. Characterization was performed using spectroscopic techniques, including 1H and 13C NMR, homonuclear and heteronuclear correlation experiments, IR and UV. Molecular docking was carried out using AutoDock Vina implemented in UCSF Chimera version 1.16 against the HDAC6 protein structure (PDB: 5EDU). 2D protein-ligand interaction diagrams were generated with Maestro, and validation was conducted by redocking trichostatin A into the HDAC6 active site. Additionally, the compounds were evaluated in cancer cell lines (MDA-MB-231, MCF-7 and NIH/3T3), and healthy cells using lymphocytes from healthy volunteers. In the in vitro experiments, the compounds evaluated showed cytotoxic activity against the BC cell lines MCF-7 and MDA-MB-231 and the non-malignant cells 3T3/NIH. Compounds 5, 8a-c exhibited antiproliferative activity comparable to that of cisplatin and doxorubicin. Molecular docking studies showed that compounds with the 3-benzoylcoumarin scaffold had favorable affinity with catalytic domain of HDAC6 and whose interactions are similar to those found in belinostat. Compounds 5, 8b, 8c, 4c, and 8a exhibited higher viability against nonmalignant cells (leukocytes), with percentages ranging from 73-87%, demonstrating 3-4-fold lower potency than belinostat against healthy cells.