Structural design and cytotoxic profiling of a novel 1,3,4-thiadiazole derivative targeting MCF-7 and HCT-116 cell lines: synthesis, cytotoxicity, and in silico study

Abstract

Cancer remains a leading cause of mortality worldwide, necessitating the continuous development of more effective and selective therapeutic agents. Among heterocyclic scaffolds, 1,3,4-thiadiazole derivatives have attracted considerable attention due to their diverse pharmacological properties and favorable physicochemical characteristics. In this study, a novel thiadiazole-based compound namely 2-((5-acetamido-1,3,4-thiadiazol-2-yl)thio)-N-(naphthalen-2-yl)acetamide, was successfully synthesized in excellent yield (99%) and high thermal stability and was fully structurally characterized using FT-IR, NMR, and mass spectrometry. The anticancer potential of the synthesized compound was evaluated in vitro against three human cancer cell lines, namely breast adenocarcinoma (MCF-7), colorectal carcinoma (HCT-116), and hepatocellular carcinoma (HepG-2), using the MTT assay. The compound exhibited pronounced cytotoxic activity against MCF-7 and HCT-116 cell lines, with IC50 values of 1.07 ± 0.03 µM and 2.09 ± 0.55 µM, respectively, demonstrating superior potency compared to the reference drug doxorubicin. In contrast, no significant activity was observed against HepG-2 cells, indicating a degree of selectivity. These findings highlight the potential of the 1,3,4-thiadiazole scaffold as a promising platform for the development of novel anticancer agents with enhanced efficacy and selectivity. In silico investigations, including molecular docking, molecular dynamics simulations, and MM/GBSA analysis, revealed stable binding of the synthesized compound within the VEGFR2 active site, supported by favorable binding free energy and key ligand–residue interactions.