Novel salicylamido sulfonamides as CD73 immune checkpoint inhibitors: Synthesis and in vitro biological evaluation.

Abstract

The immune checkpoint enzyme CD73 plays a crucial role in the adenosine (ADO) metabolic pathway by catalyzing the conversion of AMP to adenosine. Dysregulated CD73 activity elevates extracellular ADO in the tumor microenvironment, driving immunosuppression and tumor immune evasion, highlighting CD73 as a key immunotherapeutic target. In this study, we report the design and synthesis of a novel series of salicylamido sulfonamide-based small-molecule CD73 inhibitors. The in vitro CD73 inhibitory assay reveals that SA-41 and SA-26 exhibited potent activity with IC50 values of 2.83 ± 0.45 μM and 2.96 ± 0.46 μM, respectively. Molecular docking and dynamic simulations revealed that SA-26 maintained stable interactions with CD73 throughout a 100-ns simulation with no significant deviation. Furthermore, in silico ADME analysis indicated that both lead compounds possess favourable drug-like properties, with no Lipinski's rule-of-five violations, balanced lipophilicity, and acceptable predicted oral absorption, supporting their pharmacokinetic potential. These findings highlight SA-26 and SA-41 as promising candidates for further development as non- nucleotide-based small-molecule CD73 inhibitors.