Design, synthesis, and molecular docking evaluation of novel pyrimidine-thiadiazole glycosides as potential anticancer agents.

Abstract

A series of novel pyrimidine-thiadiazole conjugates incorporating carbohydrate-based 1,3,4-thiadiazole thioglycosides were synthesized and analyzed using (IR), (¹H-NMR) and (¹³C-NMR) spectroscopy. The synthesized compounds were evaluated for their cytotoxic activity against human liver (HepG2), breast (MCF-7), and lung (A549) cancer cell lines. Compound 10 showed the strongest activity with IC₅₀ values of 10.73 ± 2.04 mM (HepG2), 9.10 ± 1.97 mM (MCF-7), and 9.25 ± 2.94 mM (A549). while 6 and 7 demonstrated moderated activity. In contrast, the reference drug doxorubicin exhibited higher potency, with IC₅₀ values of 3.71 ± 1.12 mM (HepG2), 2.68 ± 0.11 mM (MCF-7), and 3.22 ± 0.22 mM (A549). Molecular docking studies revealed compound 10 had favorable binding profile with an S-score of -6.33 kcal/mol and RMSD of 3.10 Å, forming key interactions including hydrogen bonding with GLU 142, H-acceptor interaction with GLY 104, and π-H interaction with HIS 141. Compound 5 also exhibited strong binding interactions (S-score = -5.87 kcal/mol) with multiple metal and ionic interactions, whereas compounds 6, 7, and 11 displayed comparatively weaker binding affinities. These results indicate that compound 10 is the most promising candidate in this series, with both enhanced cytotoxic activity and favorable docking interactions, suggesting that pyrimidine-thiadiazole hybrids represent a valuable scaffold for further anticancer drug development.