CuI/PPA‐Catalyzed Synthesis of Novel Sulfur‐Containing Quinoline Isosteres: In Silico and DFT Analyses

The promising approach toward the synthesis of novel sulfur‐based quinoline and benzoquinoline isostere molecules. The condensation reaction involves 4‐chloro‐2,8‐dimethylquinolines or 4‐chloro‐2‐methylbenzo[h]quinoline and corresponding o‐thiosalicylic acid and 2‐mercaptonicotinic acid, either in ethanol (as a solvent) or under solvent‐free (neat) conditions. This results in the formation of an intermediate, which yields significantly better results when using neat solvent‐free conditions. The intermediates then undergo cyclization using polyphosphoric acid (PPA). Notably, the sulfur‐based quinoline and benzoquinoline isosteres are prepared through a highly efficient one‐pot methodology using CuI/Cs2CO3/DMSO conditions, which yields higher than the PPA condition through a step‐by‐step method. The synthesized novel sulfur‐containing isosteres are further analyzed through quantum chemical calculations of the frontier molecular orbitals (FMOs) and molecular electrostatic potential (MEP) using the M06‐2X method with a 6‐311 + G (d, p) basis set in water. Additionally, in silico analyses are performed in detail to predict the potential biological activity of the synthesized molecules through molecular docking and MM‐GBSA analysis against the CDK8/CycC complex. Furthermore, ADME parameters have been analyzed, and all the final cyclized molecules show the most promising drug‐like properties, inspiring further research in medicinal chemistry.