Development of novel triconjugates fusing melatonin/isatin/N-acylhydrazone targeting colorectal cancer: design, synthesis, biological, and in silico ADME/Tox profiling

Abstract

Herein, a new library of triconjugates linked melatonin with the biological active cores of isatin and N-acylhydrazone were designed, synthetized, and their biological activity was evaluated in human colorectal cancer cells. All compounds were screened to determine the potential at a single dose of 100 µM against human colon adenocarcinoma SW480 cells, finding one compound 3e which caused 100% inhibition and a certain grade of lethality at the conditions evaluated. In addition, the most active and soluble hybrids were further assessed using a five-dose scheme in the same colon cancer cells, and non-malignant human colon epithelial cells (NCM460) to establish the selective potential, finding that hybridized molecules 3e, 3g, and 3l were more cytotoxic than parental compounds and 4-fold more selective than the reference drug (5-fluorouracil, 5-FU) which shows that molecular hybridization remains as a valuable tool to produce novel chemical entities that may result in advances in medicine. Lastly, according to a theoretical analysis on drug-like properties, pharmacokinetics, and toxicology, for the most promising hybrid 3e would show a strong possibility of moving on to further preclinical research. Our results clearly demonstrated the effectiveness of melatonin/isatin/N-acylhydrazone triconjugates, with the 2-hydroxyphenylsubstituted compound in particular serving as a prototype drug for future investigations into innovative therapeutic treatments for colorectal cancer.