Unveiling acetamide coupled benzothiazole hydrazones as potential anti-proliferative agents: an experimental and computational approach.

A series of benzothiazole acetamide hydrazones (8a-p) was synthesized and evaluated for anti-proliferative activity against various human cancer cell lines, including a pancreatic ductal adenocarcinoma (CAPAN-1), a colorectal carcinoma (HCT-116), a leukemia (HL60), a glioblastoma (LN229), a T lymphoblast (Molt-4), a non-small cell lung cancer (NCI-H460), and a B lymphoblast (Z138) cell line. Among the tested derivatives, compounds 8l, 8n, and 8o emerged as lead compounds, exhibiting cytotoxicity across multiple cell lines. Notably, compound 8o demonstrated selective cytotoxicity towards Z138 and LN229 cell lines, with IC50 values of 3.75 ± 1.44 and 4.39 ± 0.49 µM, respectively. The most active compounds in in vitro analysis exhibited the highest binding affinity in molecular docking studies. Compound 8o revealed effective binding to topoisomerase IIα (TOPO IIα) having an affinity of -9.7 kcal mol-1. Compound 8n displayed extended-target engagement, with the highest number of binding interactions inside the active pocket of TOPO IIα with an affinity of -9.9 kcal mol-1, along with the highest softness value (0.69 eV-1), underscoring its potential as a promising anti-cancer candidate corresponding to its broad spectrum in vitro cytotoxicity profile. The electronic properties, and pharmacokinetic behavior of the synthesized compounds were assessed through comprehensive in silico DFT (Density Functional Theory) and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analysis, supporting their candidacy for further development as anti-cancer therapeutics.