Rational Design and Computational Evaluation of Sulfonamide-Quinoline Derivatives as Multi-Targeted Anti-Cancer Agents

Cancer is a principal cause of mortality globally, driven by genetic and epigenetic modifications that result in unregulated cellular proliferation. As a result of the shortcomings of current treatments, such as drug resistance and toxicity, this study focuses on the rational design of four A, B, C and D series of novel sulfonamide-quinoline derivatives bearing different amino linkers targeting key cancer-associated enzymes: carbonic Anhydrase IX (CAIX), Aurora Kinase A (AURKA), and Aurora Kinase B (AURKB). Molecular docking studies revealed B5, B3, C5, C3, A5, and D2 as the most promising inhibitors that showed strong binding affinities for all three target enzymes. In addition, A2, A6, B6, D3, and D6 showed selective inhibition of AURKA and AURKB. Calculations of the pharmacokinetic parameters of the hybrids were also performed, which showed favorable results. Toxicity profiling showed that A2, B4, B5, B6, D4, D5, and D6 were less toxic than Sitamaquine, but all needed optimization except for respiratory toxicity. Most compounds had good GI absorption, while B4, D4, D5, and D6 would likely require formulation adjustment to enhance their bioavailability. This study indicates that sulfonamide-quinoline derivatives are promising multi-target anti-cancer agents and deserve further in vitro and in vivo studies.