Design, Synthesis, and Biological Evaluation of Novel Quinazoline-Thiazole Hybrids As Potential Anticancer Agents

A convenient synthetic route was developed for the preparation of structurally diverse quinazolinone-thiazole hybrids using a common thiosemicarbazide intermediate (2), which underwent cyclization with different electrophiles to afford three series of derivatives (4a-e/6, 8a-c, and 11a,b/13). The structures of all synthesized compounds were confirmed by IR, NMR, MS, and elemental (CHN) analyses. The cytotoxic activity of the obtained compounds was evaluated against HCT-116 human colon cancer cells using the MTT assay after 24 h of incubation. Compounds 4b (IC₅₀ = 3.82 µM), 4a (IC₅₀ = 4.07 µM), and 11b (IC₅₀ = 4.09 µM) were the most active derivatives, showing activity comparable to doxorubicin (IC₅₀ = 4.17 µM), while compound 6 also showed good activity (IC₅₀ = 5.92 µM). Preliminary structure-activity relationship analysis indicated that electron-donating aryl substituents such as methyl and methoxy groups enhanced the activity in the 4-series, whereas electron-withdrawing substituents such as chloro, bromo, and nitro reduced it; in the 11-series, the ethyl ester derivative 11b was more potent than the corresponding acetyl derivative 11a. Cytotoxicity against the non-tumor LLC-MK2 cell line showed that compounds 4a, 4b, 6, and 11b exhibited IC₅₀ values > 100 µM, indicating a favorable preliminary selectivity toward the cancer cell line. Molecular docking against human uridine 5'-monophosphate synthase (UMPS, PDB: 7OUZ) supported the observed activity trends, and in silico ADMET prediction suggested acceptable drug-like and pharmacokinetic properties. Overall, compounds 4a, 4b, and 11b emerged as promising anticancer candidates for further mechanistic and selectivity studies.