Simplification and Derivatization of Quinoline-Containing M41 Lead to the Discovery of NADPH Oxidase Isoform-Selective Inhibitors Effective in Cancer Cells

NADPH oxidases (NOXs) are attractive but challenging drug targets. Starting from M41 and its analog MC4876, we synthesized quinoline-based derivatives. SAR studies revealed that modifications at the quinoline C2 position and the amine-moiety influenced potency and isoform preference. Boc-protected analogs preferred NOX5, (compound 1a: IC50 = 1.6 μM), whereas deprotected derivatives favored NOX2. Replacing piperidine with tetrahydropyran afforded 1e, a selective NOX1 inhibitor (IC50 = 3.4 μM). The bisquinoline derivative 2a emerged as the most potent, selective NOX2 inhibitor (IC50 = 1.4 μM; cellular EC50 = 0.89 μM). Computational studies support binding at the NADPH site and attribute 2a′s enhanced potency to additional interactions. MC4876 displayed antiproliferative activity, reducing glioblastoma cell viability, glucose uptake, HK2 expression, and mesenchymal markers, while lowering ROS and inducing mitochondrial dysfunction and DNA damage in U937 cells. These findings identify quinoline as tunable scaffolds for isoform-selective NOX inhibition, with 1e and 2a as promising leads.