Chemistry Proceedings

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In the pursuit of novel anticancer agents, a new series of 1,3,4-thiadiazole derivatives were designed and synthesized, aiming to inhibit tumor necrosis factor-alpha (TNF-α), a pro-inflammatory cytokine implicated in cancer progression. 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 7a–7d) 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. Molecular docking studies 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.

The TEA domain (TEAD) transcription factors are important parts of the Hippo signaling cascade and are important therapeutic targets in cancer research because they help control cell growth, avoid apoptosis, and cause tumors to form. In this study, a structure-based virtual screening method was used to find new TEAD antagonists in the ChemDiv natural product database. Using the AutoDock platform for molecular docking, we ranked eight candidate ligands—16956, 726, 5271, 11768, 12384, 15598, 15641, and 3622—based on strong binding affinities, as shown by docking energies that ranged from −8.02 to −8.49 kcal/mol. Swiss ADME’s full in silico ADMET profile showed that all of the selected compounds had good pharmacokinetic properties and did not break Lipinski’s rule of five, which means they would be quite bioavailable when taken by mouth. Two lead candidates, 11768 and 15598, did not pass across the blood-brain barrier (BBB) and were not substrates for P-glycoprotein. This means that they had less exposure to the central nervous system and a lower chance of developing multidrug resistance. Later molecular dynamics (MD) simulations verified that the ligand TEAD complexes were stable in their shapes, and MMGBSA (Molecular Mechanics/Generalized Born Surface Area) free energy calculations indicated that they had high-affinity binding. Principal component analysis (PCA) and free energy landscape tests helped to explain even more the dynamic behavior and thermodynamic landscapes of the complexes. This integrated computational technique helped us find strong, drug-like TEAD inhibitors in a logical way. It also gave us a solid base for further preclinical testing and structural optimization in the creation of targeted anticancer drugs.