Synthesis, DFT Studies, and Biological Evaluation of New Quinazoline-1,3,4-Thiadiazole Derivatives as Anti-proliferative Agents

Autophagy is a conserved catabolic process in which cells degrade and recycle their cytoplasmic constituents, including damaged or unnecessary proteins and organelles. Autophagy and Lung's cancer have a convoluted and poorly understood relationship. ULK1, known as autophagy initiation kinase, has been found to play a role in the development and progression of non-small cell lung cancer (NSCLC).

The primary objective of this study was to identify a novel thiadiazole derivative that inhibits ULK.

Different thiadiazole derivatives were synthesized and characterized using FT-IR, ¹H-NMR, and Mass spectroscopy. The HOMO, LUMO, and their energies were predicted using DFT (Density Functional Theory) calculations. These compounds were applied to tested on the NSCLC A549 cell lines, and their cytotoxic effects were measured using the MTT dye uptake method.

Different thiadiazole derivatives were successfully synthesized and studied for anticancer activity. Most of them displayed activity against non-small lung cancer A549 cell lines, with respective IC₅₀ values of 12.2 µM to 208.06 µM. The IC₅₀ values for compounds 7d, 7 g, 7 h, 7f, and 7i were found to be 12.2, 16.35, 20.61, 20.76, and 22.01 µM, respectively. We optimized HOMO and LUMO plots for the new compounds using a theoretical approach.

According to preliminary bioassays, most compounds showed excellent antitumor activity and potent ULK enzyme inhibition.