Investigating chronic myeloid leukemia therapeutics: AI-optimized design and synthesis of 4-methylthiazole-2-amine...

A series of 4-methylthiazole-2-amine derivatives (3a-3f, 6g-j and 7) were prepared via a Hantzsch-type multicomponent reaction and characterized by FT-IR, ¹H-NMR and ¹³C-NMR spectroscopy techniques. The cytotoxic effects of the synthesized products on the chronic myeloid leukemia K562 and U937 cell lines were tested using the MTT assay. Compounds 3a, 3b, 3c, 6g, 6h and 6i exhibited high cytotoxic potential with IC₅₀ values ranging from 1.5 to 5 0 µM, which showed a dose-dependent inhibition. Stable ligand-receptor interaction was observed by molecular docking studies against the chosen CML-associated proteins (2GQG, 5MO4, 2AZ5 and 5MAR) with the highest docking scores obtained for 6h and 6i (-8.37 and -8.97 kcal mol^-1, respectively). Strong binding affinities (ΔG = -53.36 kcal mol^-1) were confirmed by MM-GBSA calculations. Further, density functional theory (by using B3LYP/6-311G basic function set) was used to gain information on the electronic configurations, HOMO-LUMO gaps and charge distribution, which favored stability of the molecules and reactivity. The combined experimental and computational findings indicated that compounds 6h and 6i are potential scaffolds that can be used to develop new thiazole-based anticancer agents against chronic myeloid leukemia.