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. 2025 Nov;106(5):e70203.
doi: 10.1111/cbdd.70203.

Synthesis, Cytotoxic Activity, and Molecular Docking Study of New Thiazole-Incorporated Indenopyridazine Derivatives as Potential Antiproliferative Drugs

Alaa M Alqahtani  1 , Sultan I Alkbaysi  1 , Mariam Mojally  1 , Amgad Albohy  2 , Hussni Muathen  1
Affiliations

Synthesis, Cytotoxic Activity, and Molecular Docking Study of New Thiazole-Incorporated Indenopyridazine Derivatives as Potential Antiproliferative Drugs

Alaa M Alqahtani et al. Chem Biol Drug Des. 2025 Nov.

Erratum in

Abstract

Cancer is among the leading causes of death in the world today. Several strategies were used to control cancer including chemotherapy, radiotherapy and targeted therapy. Among the problems related to antiproliferative chemotherapy against cancer is the medication resistance which require continuous generation of new agents. These new potential agents could be extracted from natural sources or prepared synthetically. This research represents the preparation of new heterocycles incorporating an indenopyridazine nucleus as potential antiproliferative agents. The synthetic strategy was initiated by the treatment of ninhydrin with cyanoacetohydrazide resulting in the formation of the key intermediate indeno[2,1-c]pyridazine scaffold 4, which undergoes condensation with various nitrogenous nucleophilic reagents (namely: phenyl hydrazine, substituted benzohydrazide, and thiosemicarbazide). Cyclization of thiosemicarbazone derivative 8 with ethyl bromoacetate furnished the target compound thiazolin-4-one derivative 9, which was condensed with three 5-aryl-1H-pyrazole-4-carbaldehydes to furnish the corresponding 5-arylidene-thiazolin-4-one derivatives 11a-c. In addition, thiosemicarbazone derivative 8 undergoes reactions with α-chloroesters 12 or α-chloroketones 14 to yield the indenopyridazine-thiazole hybrids 13 and 15, respectively. The cytotoxic activity of the targeted indeno[2,1-c]pyridazine compounds was explored against four cancer cell lines in vitro. Indenopyridazine-thiazolin-4-one hybrid 11c exhibited the highest cytotoxicity against HepG2 (IC50 = 7.43 μM) and MCF-7 cells (IC50 = 4.37 μM). Their IC50 values were very close to the reference drug 5-fluorouracil. Also, compound 7b was found to show a very strong cytotoxic effect against HepG2 (IC50 = 10.20 μM) and MCF-7 (IC50 = 7.39 μM). Moreover, molecular docking indicated that compounds 11b, 7b, and 11c had the best docking score against vascular endothelial growth factor recetor-2 (VEGFR-2) which is the potential target predicted by target fishing.

Keywords: HepG2; docking; fluorouracil; indenopyridazine; ninhydrin.

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References

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