Novel monastrol/melatonin hybrids as a new approach for colorectal cancer intervention: design, synthesis, biological activity, and drug-likeness modeling studies

Abstract Considering the important increase in the incidence and mortality of colorectal cancer, it is necessary to develop new strategies in the search for new alternatives against this disease. Hence, we designed and synthesized a new series of monastrol/melatonin hybrids and evaluated them in vitro and in silico to determine the potential of these new chemical entities on this type of cancer. To achieve this goal, the different compounds were evaluated in human colorectal adenocarcinoma cells SW480, while establishing the selective potential of the hybrids through the nonmalignant human colon mucosal epithelial cell line (NCM460). According to the results, hybrids 6a , 6c , 6i , and 6j displayed the best response, with IC 50 values in the range of 5.2 and 6.3 μM, inducing important changes depending on concentration and time. In addition, these compounds were extremely active in comparison to the single molecules, and they were slightly more selective than the reference drug (5 fluorouracil, 5-FU). Besides, an optimal pharmacokinetic and toxicological profile was also estimated for hybrids 6a , 6c , 6i , and 6j . Altogether, novel hybrids of monastrol-MLT, in particular, 6a (-H), 6c (3-OMe), 6i (3,4-OMe), and 6j (3,5-OMe) could be addressed as starting points for further pharmacological studies concerning to combat colorectal cancer.