Design and Synthesis of Tri-substituted Imidazole Derivatives as CD73 Inhibitors for Their Anticancer Activity

Abstract

Background:Monoclonal antibodies licensed by the US Food and Drug Administration (FDA) target diverse biological targets relevant to immuno-oncology, and small compounds in clinical trials target various aspects of immuno-oncology. Several small compounds that target CD73 are at various stages of clinical studies. Several imidazoles are currently being utilized to treat malignancies, including Dacarbazine, Zoledronic acid, Mercaptopurine, and others. As a result, we evaluated the cytotoxicity of modified tri-phenyl imidazoles against breast cancer cell lines, as well as conducted virtual tests.Methods:We used Accelrys Drug Discovery Studio 3.5 software to undertake molecular docking, ADMET, and molecular properties studies on 68 proposed imidazole derivatives. The synthesized compounds' binding mechanisms were investigated against the CD73 protein (PDB Code: 4H1S). To find the drugs with the best pharmacokinetics, researchers assessed ADMET solubility, BBB penetration, hepatotoxicity, PPB binding, and polar surface area. The MDA-MB-231 breast cancer cell line was treated with these produced compounds, and the MTT test method was used to determine the IC50 values.Results:The selected 14 compounds showed good binding in the active site of CD73 by forming Hbonds with amino acid residues, according to molecular docking studies. Breast cancer cell lines were treated with substituted tri-phenyl imidazole derivatives, which displayed anticancer activity. Compounds 3a and 3h, which had an electron-donating group at the 2nd and 3rd positions and p-substitutions of the chloro and nitro groups, respectively, showed considerable anticancer action.Conclusion:Fourteen imidazole derivatives were produced and tested against breast cancer cell lines based on in-silico research. The MDA-MB-231 cell line was strongly suppressed by compounds 3a and 3h. In-vitro enzyme inhibition experiments revealed that only 3h demonstrated considerable inhibition.