Molecular modelling, cytotoxic activity, and carbonic anhydrase inhibition of new pyridazine-thiazole hybrid compounds

A series of novel pyridazine-thiazole compounds 6 , 7 , 9 , and 10 were synthesized by introducing various thiazole ring systems into the precursor 4-(pyridazin-3-yl)amino)benzohydrazide compound 4 . The DFT/B3LYP optimized structures of the synthesized hybrids exhibited a non-planar geometry. Frontier orbital structures of the studied derivatives were strongly influenced by structural modifications. For example, in the ester 3 and hydrazide 4 analogues, the HOMO was localized on the phenylamino-pyridazine, whereas the LUMO was mainly centered on the cyano-pyridazine moiety. While in the thiosemicarbazide hybrid 5 , the HOMO has shifted toward sulfur- and nitrogen-rich regions, indicating enhanced intramolecular charge-transfer character. The in vitro cytotoxic activity of the synthesized analogues against HepG2, HT-29, MCF-7, and WI-38 cell lines showed that analogue 10b exhibited potent activity (IC₅₀ = 22.39 ±0.16 μM) against HepG2, while analogue 8 disclosed the good activity toward HT-29, (IC₅₀ = 16.54 ±0.38 μM) and analogue 10a revealed proper efficacy (IC₅₀ = 16.44±0.31 μM) against MCF-7 higher than that of the reference doxorubicin. Besides, the carbonic anhydrase enzymes inhibitory potential against the tumor-related isoforms (CA IX and CA XII) presented hybrids 5 , 7a , 10a , and 10c as good CA IX inhibitors, comparable to the reference inhibitor acetazolamide (AZA). Meanwhile, docking with human 5FL4 protein revealed that the pyridazine-hydrazinyl analogues displayed proper bindings due to their more separate electron density and effective interactions. The pharmacokinetics SwissADME in silico studies indicated that the low molecular weight conjugates respect Lipinski’s rule of five, with optimal value of lipophilicity (iLOGP < 3.27), and exhibit blood-brain barrier permeability. While bulky derivatives showed a reduced gastrointestinal absorption (GI) absorption with increased molecular weight, topological polar surface area.