DESIGN, SYNTHESIS, MOLECULAR DOCKING, ADMET PREDICTION AND IN VITRO ANTICANCER EVALUATION OF NOVEL CURCUMIN–QUINOLINE HYBRID DERIVATIVES

The present study successfully demonstrated the design, synthesis, and evaluation of a series of novel curcumin–quinoline hybrid derivatives as potential anticancer agents. The study adopted an integrated drug discovery approach combining rational molecular design, molecular docking, ADMET prediction, chemical synthesis, spectral characterization, and in vitro cytotoxicity evaluation to identify promising lead molecules. The molecular docking results revealed that the designed hybrid derivatives exhibited favourable interactions with the selected cancer-associated targets, namely EGFR, VEGFR-2, and BCL-2. Among the synthesized compounds, CQ-5 consistently showed the strongest binding affinity, indicating its potential to effectively inhibit multiple pathways involved in tumour progression. The ADMET analysis further demonstrated that the designed molecules possessed acceptable drug-like properties, with good predicted oral absorption and a favourable preliminary safety profile. The synthesized derivatives were obtained in satisfactory yields and their chemical structures were successfully confirmed through FTIR, ¹H NMR, and Mass Spectrometry. The in vitro cytotoxicity study demonstrated that the hybrid molecules possessed improved anticancer activity compared with the parent curcumin scaffold. In particular, CQ-5 exhibited the highest biological activity, which correlated well with its molecular docking and ADMET results. This consistency between computational predictions and biological evaluation highlights the effectiveness of the adopted drug design strategy. Overall, the findings of this study suggest that molecular hybridization of curcumin and quinoline is a promising strategy for the development of novel multi-target anticancer agents. The fluoro-substituted derivative CQ-5 emerged as the most promising lead compound due to its balanced combination of strong target binding, favourable pharmacokinetic properties, and enhanced cytotoxic activity. Although the present investigation provides encouraging preliminary evidence, further studies involving in vivo pharmacological evaluation, pharmacokinetic analysis, toxicity studies, and detailed mechanistic investigations are required before clinical application can be considered. Nevertheless, the current work provides a strong scientific foundation for the continued development of curcumin–quinoline hybrid molecules as potential therapeutic candidates for cancer treatment.

[1]             Aggarwal BB, Harikumar KB. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against human diseases. Int J Biochem Cell Biol. 2009;41(1):40–59. [2]             Hewlings SJ, Kalman DS. Curcumin: A review of its effects on human health. Foods. 2017;6(10):92. [3]             Kunnumakkara AB, Bordoloi D, Padmavathi G, et al. Curcumin, the golden nutraceutical: multitargeting for multiple chronic diseases. Br J Pharmacol. 2017;174(11):1325–1348. [4]             Talele TT. Opportunities for tapping into three-dimensional chemical space through molecular hybridization. J Med Chem. 2020;63:13291–13315. [5]             Lionta E, Spyrou G, Vassilatis DK, Cournia Z. Structure-based virtual screening for drug discovery: principles, applications and recent advances. Curr Top Med Chem. 2014;14:1923–1938. [6]             Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7:42717. [7]             Pires DEV, Blundell TL, Ascher DB. pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J Med Chem. 2015;58:4066–4072. [8]             Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65:55–63. [9]             Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;144(5):646–674. [10]         Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2024: GLOBOCAN estimates of incidence and mortality worldwide. CA Cancer J Clin. 2024.