Cystic fibrosis (CF) is caused by the functional expression defect of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Despite the recent success in CFTR modulator development, the available correctors only partially restore the F508del-CFTR channel function, and several rare CF mutations show resistance to available drugs. We previously identified compound 4172 that synergistically rescued the F508del-CFTR folding defect in combination with the existing corrector drugs VX-809 and VX-661. Here, novel CFTR correctors were designed by applying a classical medicinal chemistry approach on the 4172 scaffold. Molecular docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted to propose a plausible binding site and design more potent and effective analogs. We identified three optimized compounds, which, in combination with VX-809 and the investigational corrector 3151, increased the plasma membrane density and function of F508del-CFTR and other rare CFTR mutants resistant to the currently approved therapies.