An improved and rapid synthesis of mefenamic acid based indole derivatives has been achieved via the ligand free Cu-catalyzed coupling-cyclization method under ultrasound irradiation. This simple, straightforward and inexpensive one-pot method involved the reaction of a terminal alkyne derived from mefenamic acid with 2-iodosulfanilides in the presence of CuI and K<sub>2</sub>CO<sub>3</sub> in PEG-400. The reaction proceeded via an initial CC bond formation (the coupling step) followed by CN bond formation (the intramolecular cyclization) to afford the mefenamic acid based indole derivatives in good to acceptable yields. Several of these compounds showed inhibition of PDE4 in vitro and the SAR (Structure Activity Relationship) within the series is discussed. The compound 3d has been identified as a promising and selective inhibitor of PDE4B (IC<sub>50</sub> = 1.34 ± 0.46 µM) that showed TNF-α inhibition in vitro (IC<sub>50</sub> = 5.81 ± 0.24 µM) and acceptable stability in the rat liver microsomes.