Design, Synthesis and In Vitro Anticancer Activity of Benzo[c]chromen-6-one-linked 1,2,3-Triazole

Background: The 1,2,3-triazole hybrids and conjugates containing natural or related compounds motif demonstrate diverse biological activities, including anticancer, antimicrobial, anti-tubercular, antiviral, antidiabetic, antimalarial, anti-leishmanial, and neuroprotective ones. Among a wide range of pharmacological applications, considerable attention is paid to the study of anticancer activity. In anticancer research, combining 1,2,3-triazole with other motifs, previously demonstrating antiproliferative activity into one hybrid molecule, is a common strategy for the creation of new bioactive molecules. The CuAAC (copper-catalyzed azide-alkyne cycloaddition) is a very convenient reaction for the rapid construction of drug-like 1,2,3-triazoles at room temperature in a short time. Methods: Based on the pharmacophore strategy, a virtual combinatorial library of benzo[c]chromen-6-one linked 1,2,3-triazole derivatives was designed and lead-likeness and molecular analysis were performed. Selected compounds were synthesized via CuAAC click reaction and the chemical structures of all new 1,2,3-triazole hybrids were proved by H-1, C-13 NMR, MS and elemental analyses. Their anti-cancer activity in the human cancer cell lines was evaluated using the MTT assay. Results: A virtual in silico screening of novel benzo[c]chromen-6-one linked 1,2,3-triazole was carried out in order to discover potential antitumor agents. The synthesis of promising compounds was carried out via CuAAC reaction, and their antineoplastic action was studied on human tumor cells of HL-60, HCT116, HCT116 p53-/-, Skov3, U251, MDA231 lines. Their cytotoxic effect towards pseudo-normal human cells of HaCaT line was also evaluated. 2-((1H-1,2,3-triazol-4-yl)methoxy)-6H-benzo[c]chromen-6-one (4c) with pyridin-3-yl substituent demonstrated the highest antiproliferative action in vitro (IC50 79.5 mu M) towards human leukemia cells of HL-60 line, while all tested compounds at >100 mu M concentration were tolerant for non-tumor human keratinocytes of HaCaT line. Conclusion: A novel benzo[c]chromen-6-one linked 1,2,3-triazoles exhibiting promising in vitro anti-cancer activity and low toxicity were designed. This study suggests new scaffolds for the development of anti-cancer drugs, which could be easily further optimized via the convenient synthetic procedure.

Automated summary

This study designed novel benzo[c]chromen-6-one linked 1,2,3-triazoles exhibiting promising in vitro anti-cancer activity and low toxicity, providing new scaffolds for the development of anti-cancer drugs.