Design, Synthesis and Cytotoxic Evaluation of New Quinolinedione Derivatives as Potential Candidates for the Treatment of Cancer

Abstract

Background:

Carbonic anhydrase IX (CAIX) affected by hypoxia and thus lead to upregulated in many types of tumors and thus helps in maintain tumor pH balance under these conditions. Pharmacologic inhibition of CAIX has been shown in mouse models to slow tumor growth, curb metastasis, and limit tumor stem cell expansion. Therefore, inhibiting the overexpression of CA, particularly CA IX, consider a promising anticancer therapy.

Objective:

The primary objective of this study was to design and synthesis of a set of new quinolinedione derivatives (5a-c), study antiproliferative activity by MTT assay against HCT116 cell lines and MCF-7 cell lines and molecular docking studies to prioritize candidates’ compounds with the highest predicted binding.

Methods:

The synthesis of new quinolinedione derivatives (5a-c) through derivatives bearing methylsulfonyl aniline scaffolds, characterized via TLC, melting point, and spectral data acquisition (HNMR, and CNMR), and cytotoxic evaluated for the synthesised derivatives using antiproliferative activity by MTT assay against HCT116 cell lines and MCF-7 cell lines.

Results:

Among the tested compounds, 7-methoxy-3,4-dihydroquinolin-2(1H)-one (compound 5c) exhibited markedly stronger antiproliferative activity in HCT116 cells (IC₅₀ = 0.98 μM) and MCF-7 cell lines (IC₅₀ = 1.39 μM) versus acetazolamide (IC₅₀ = 1.69 μM, IC₅₀ = 2.45 μM). While, both compounds 5a and 5b showed a close cytotoxic activity results to acetazolamide. These results position quinolinedione derivatives (5a-c) as a promising starting point for further development as an anticancer agent. Docking study indicated that 5c achieved good S-scores (-6.211) in compare with acetazolamide (-5.574), suggesting stronger affinity for the CA IX active site. The substituted methoxy group and quinolinedione scaffold appear to enhance flexibility and receptor interactions.

Conclusion:

Overall, the quinolinedione derivatives (5a-c) were effectively synthesized and exhibit meaningful CA IX inhibition and cytotoxic activity, supporting their further evaluation as potential anticancer leads.