Cystic fibrosis (CF) is a life-threatening hereditary disease caused by mutations in the CF trans membrane conductance regulator (CFTR) gene. The commonly utilized medication for CF is a potentiator that restores CFTR function by stabilizing the channel in open conformation. A multistep synthesis method has been demonstrated here for synthesizing 2-methyl-3-carboxamide-4-quinolones having potential activities on CF. The synthesized molecules were obtained in quantitative yield and purified using recrystallization techniques without column purification. An extensive computational analysis was carried out to access the potential of 2-methyl-3-carboxamide-4-quinolones as potentiators. The computational analysis using molecular docking, classical and membrane-embedded molecular dynamics simulations in different lipid environments, and MM-PBSA revealed that the molecule 4d formed a stable complex. The binding free energies from umbrella sampling simulations for standard molecules ivacaftor and GPLG1837 were −26.133 kJ/mol and −28.471 kJ/mol, respectively, while for 4d a lower free energy value was obtained (−37.852 kJ/mol), which further strengthened the candidature of 4d as a promising potentiator molecule. This research identified a hit molecule that could be utilized further in in-vitro and in-vivo studies to establish it as a potentiator against CF and also provided a suitable and efficient synthesis method for the pharmaceutical industries. © 2023 Elsevier Ltd.