Design and synthesis of tri-substituted imidazole derivatives as CD73 inhibitors for their anticancer activity

Background: US-FDA-approved monoclonal antibodies focus different biological targets related to immuno-oncology and small molecules which are in clinical trials target different immune-oncology aspects. Some small molecules targeting CD73 are in the different phases of clinical trials. Presently, several imidazoles such as Dacarbazine, Zoledronic acid, Mercaptopurine, etc. are being used in the treatment of various cancers. Hence, we explored the cytotoxicity studies of substituted tri-phenyl imidazoles against breast cancer cell line followed by virtual studies. Methods: We performed molecular docking, ADMET, and molecular properties studies for 68 designed imidazole derivatives using Accelrys Drug Discovery Studio 3.5 software. The binding modes of the designed compounds were studied against CD73 protein (PDB Code: 4H1S). ADMET solubility, BBB penetration, hepatotoxicity, PPB binding, polar surface area also studied to obtain the compounds with best pharmacokinetic properties. The breast cancer cell line MDA-MB-231 was treated with these synthesized compounds and IC50 was evaluated by MTT assay method. Results: Molecular docking studies indicate that the selected 14 compounds show good binding at the active site of CD73 by forming H-bond with amino acid residues. Substituted tri-phenyl imidazole derivatives showed anticancer activity against breast cancer cell line. Particularly, compounds 3a and 3h with electron donating group at 2nd and 3rd position with the p-substitutions of chloro and nitro group showed significant anticancer activity. Conclusion: Based on the in-silico studies fourteen imidazole derivatives were synthesized and evaluated against breast cancer cell line. Compounds 3a and 3h significantly inhibited the growth of MDA-MB-231 cell line. From the in vitro enzyme inhibition studies, only 3h showed significant inhibition.