Design, synthesis and structure-activity relationship of malonic acid non-nucleoside derivatives as potent CD73 inhibitors

[Display omitted] •A series of malonic acid non-nucleoside derivatives were designed and synthesized.•The majority of these compounds demonstrated moderate to significant inhibition activity against CD73.•Compounds 18 and 19 exhibited significant inhibition activities against hCD73 with IC50 values of 0.28 μM and 0.10 μM. High levels of extracellular adenosine in tumor microenvironment (TME) has extensive immunosuppressive effect. CD73 catalyzes the conversion of AMP into adenosine and regulates its production. Inhibiting CD73 can reduce the level of adenosine and reverse adenosine-mediated immune suppression. Therefore, CD73 has emerged as a valuable target for cancer immunotherapy. Here, a new series of malonic acid non-nucleoside derivatives were designed, synthesized and evaluated as CD73 inhibitors. Among them, compounds 18 and 19 exhibited significant inhibition activities against hCD73 with IC50 values of 0.28 μM and 0.10 μM, respectively, suggesting the feasibility of replacing the benzotriazole moiety in the lead compound. This study explored the novelty and structural diversity of CD73 inhibitors.