Synthesis, molecular modelling, and cytotoxic activity of new thienopyridazine analogues clubbed thiazole ring systems

New thieno[2,3-c]pyridazine compounds incorporating various thiazole ring systems were prepared via different synthetic approaches and their chemical structures were verified by the spectral analyses (IR, NMR, and MS). The DFT/B3LYP optimized structures of thienopyridazine hybrids displayed non-planar geometries. Structural modifications significantly influenced frontier orbital structures, with the parent aminothienopyridazinyl 3 showing HOMO–LUMO localized on the fused ring system and characterized by π-π* transitions. In contrast, the nitro-substituted analogues had a LUMO primarily localized on the benzylidene phenyl, indicating a notable separation between donor and acceptor regions. Also, the synthesized analogues were assessed for their cytotoxicity against different cancer cells, where the analogue 8 presented significant antiproliferative properties against both HT-29 and MCF-7 cells (IC₅₀ = 12.57 ± 0.31 and 17.66 ± 0.39 μM), close to doxorubicin reference. More significantly, most analogues showed high selectivity index values against WI-38 cells. Molecular docking studies against PDB:3T0Z showed binding scores (S) ranging from -4.9488 (for 4) to -7.2492 kcal/mol (for 8). The molecular docking showed that derivatives with thiazole and thiazolidinone groups exhibited enhanced binding, where such rings increased hydrophobic and pi-stacking interactions. Pharmacokinetic and drug-likeness profiles revealed that analogues 8, 9, and 10a, exhibited high GI absorption, owing to their large molecular weights and topological polar surface area. On the other hand, the compounds have not been found to cross the BBB. This suggests that the synthesized analogues are appropriate drugs against non-CNS diseases.