Sulfonylhydrazide Derivatives as Potential Anti-cancer Agents: Synthesis, In Vitro and In Silico Studies.

The synthesis of new agents for cancer treatment persists due to its global lethality. A series of thirteen derivatives, namely salicylic acid-5-sulfohydrazide (SA-SH) analogs, were designed and synthesized from 5-(chlorosulfonyl)-2-hydroxybenzoic acid via nucleophilic substitution reaction with different acid hydrazides, thiocarbohydrazide & thiosemicarbazide scaffolds. Confirmation of the designed derivative's structures employed various spectroscopic techniques (FT-IR and NMR) and elemental analysis. The newly synthesized synthons were evaluated for cytotoxic activity against HepG-2 and HCT-116 cell lines in comparison to Doxorubicin. Notably, SA-SH derivatives (5, 7, 8a, 8b and 11) exhibited significantly higher efficacy against HepG-2 and HCT-116 cell lines than other analogs. Furthermore, compound (8a) demonstrated a superior activity against HepG-2 cell lines with IC₅₀ values of 3.99 ± 0.2 μM than the reference drug, Doxorubicin, (IC₅₀ HepG-2 = 4.50 ± 0.2 µM). The molecular docking simulation of the most active SA-SH derivatives and the reference drug doxorubicin into the active site of FGFR4 (fibroblast growth factor receptor, the predominant isoform expressed in human hepatocytes) (PDB ID: 6V9C) proved the usefulness of hybridizing salicylic scaffold with SO₂ and hydrazide moieties as a promising approach in designing new anticancer agents. Finally, ADME and drug-likeness features of the most active compounds compared to positive controls were investigated to increase the success possibilities in clinical trials and they were found to be promising candidates for further investigation and development as drugs.