Halogen‐Substituted Thiourea Derivatives as CD73 Inhibitors: In Vitro and In Silico Studies

Cancer development is linked to dysregulated purinergic signaling and ectonucleotidase activity. In this work, nine 4‐bromobenzoyl‐substituted thiourea derivatives were synthesized and evaluated for ectonucleotidase inhibition. Several compounds showed sub‐micromolar to low‐micromolar inhibitory activity, with the most active derivatives strongly inhibiting human CD73. Notably, compound 4d showed inhibitory activity against both human and rat ecto‐5′‐nucleotidase. Cytotoxicity evaluation against HepG2 and HCT‐116 cancer cells showed moderate activity, while lower cytotoxicity was observed against noncancerous HEK293T cells. Molecular docking and 100 ns molecular dynamics simulations supported stable binding of the most active derivative within the CD73 active site. ADMET and DFT analyses provided insights into the pharmacokinetic and electronic properties of the synthesized compounds.