In the pursuit of novel anticancer agents, a new series of 1,3,4-thiadiazole derivatives was designed and synthesized, aiming to inhibit tumor necrosis factor-alpha (TNF-α), a pro-inflammatory cytokine implicated in cancer progression and metastasis. The synthesis involved the initial condensation of substituted anilines with chloroacetic acid to yield 2-(substituted phenylamino)acetic acids, which were then esterified and converted to hydrazides. Cyclization with carbon disulfide and further functionalization produced oxadiazole, thiadiazole, and triazole intermediates. Final thiadiazole-based derivatives (compounds 8a–8d) were obtained by alkylation with substituted phenacyl bromides.

These compounds were biologically evaluated for anticancer potential with specific focus on TNF-α inhibition, a critical target in inflammatory and tumorigenic signaling pathways. In silico docking and in vitro testing suggested strong binding affinities of the synthesized molecules to the TNF-α active site, indicating their possible role in downregulating pro-inflammatory responses associated with tumor development. Biological screening demonstrated promising cytotoxicity profiles in preliminary in vitro cancer models.

Structure-activity relationship (SAR) analysis revealed that electron-withdrawing groups (Cl and F) on the thiadiazole scaffold significantly enhanced TNF-α targeting and anticancer activity. These findings support the potential of these thiadiazole derivatives as promising anticancer agents targeting TNF-α.

Keywords: 1,3,4-thiadiazole; TNF-α inhibition; anticancer agents; synthesis; molecular docking