Imidazole-Functionalized Thieno[3,2-c]quinolines as Promising Antiproliferative Agents: Design, Synthesis, NCI-60 Screening, and Computational Analysis

Polycondensed thieno[3,2-c]quinoline scaffolds represent promising yet underexplored frameworks for anticancer drug discovery. Building on previously reported derivatives of type 7, a new series of imidazole-functionalized thieno[3,2-c]quinoline-2-carboxylates (10a–j) was rationally designed to optimize physicochemical, drug-like, and safety-related properties and synthesized through a multistep synthetic sequence. Antiproliferative activity was evaluated in vitro by using the NCI-60 human tumor cell line panel. Six derivatives displayed low-to-submicromolar mean GI50 values (0.98–5.55 μM), with compound 10c emerging as the most potent analogue (mean GI50 < 1 μM) across multiple aggressive tumor models. Integrated computational analyses, including docking, binding free-energy molecular mechanics with generalized Born and surface area calculations, molecular dynamics simulations, and density functional theory studies, supported enhanced interaction profiles and electronic adaptability of the optimized core relative to the parent series. Overall, the imidazole-functionalized thienoquinoline hybrids exhibit broad antiproliferative activity and improved predicted developability, identifying this chemotype as a valuable platform for further anticancer optimization and structure–activity investigations.