New melatonin biphenyl-linked scaffold targeting colorectal cancer: design, synthesis, biological, and ADME-Tox...

A series of melatonin biphenyl-linked conjugates was designed and synthesized using a simple, cost-effective, and environmentally friendly method. All the new compounds were evaluated for their cytotoxic or cytostatic activity against SW480 human colorectal adenocarcinoma cells. Screening at 100 μM revealed that most compounds exhibited high activity (≥60% inhibition), with compounds 3b, 3h, 4f, 4g, and 4i-l also demonstrating subtle lethality. Based on these initial results, a subset of the most active hybrids was selected for further in-depth evaluation to calculate three key parameters of cell viability: GI₅₀, TGI, and LC₅₀ values. The results showed that most compounds, except 3c and 4d, significantly outperformed the parental compound (2 and melatonin) in inhibiting cancer cell proliferation, highlighting the efficacy of hybridization in improving cytotoxic potential. Besides, it is noticeable that hybrids 4f-l exhibited superior activity compared to 5-FU, as evidenced by lower GI₅₀ values. Although hybrids 4f and 4g seemed to exert the greatest activity as demonstrated in the LC₅₀ values (70.89 ± 11.72 μM and 68.03 ± 0.46 μM, respectively), we observed that only hybrids 4j and 4l showed significant selectivity, as revealed by higher GI₅₀ concentrations over non-malignant cells (NCM460). The observed total growth inhibition and lack of LC₅₀ values in 4j and 4l suggest their potential for a cytostatic effect. Lastly, theoretical evaluations of drug-likeness, pharmacokinetic behaviour, and toxicological parameters suggest that the most promising hybrids, compounds 4j and 4l, exhibit strong potential for advancement into preclinical studies. Our findings highlight the effectiveness of a novel melatonin biphenyl-linked scaffold, with 4j and 4l structures in particular serving as prototypes for future innovative adjuvant drugs.